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The Breast Reconstruction Risk Assessment (BRA) Score tool is a risk calculator developed to predict the risk of complications in individual patients undergoing breast reconstruction. It was developed in a North American population exclusively undergoing immediate breast reconstruction. This study sought to assess the predictions of the BRA Score tool against the measured outcomes of surgery for an Australian public hospital population, including both immediate and delayed reconstructions.This was a retrospective cohort study of data from women at a single Australian public teaching hospital unit. Data from the Flinders Breast Reconstruction Database was retrieved and compared to BRA Scores calculated for each patient. Receiver operating curve area under the curve analysis was performed as well as Brier scores to compare predicted versus observed complications.BRA Score predictions were reasonable or good (C-statistic0.7, Brier score0.09) for the complications of overall surgical complications, surgical site infection (SSI) and seroma at 30 days, and similarly accurate for prediction of the same complications for implant reconstructions at 12 months. There were similar findings between delayed and immediate reconstructions.The BRA Score risk calculator is valid to detect some risks in both patients undergoing immediate and delayed breast reconstruction in an Australian public hospital setting. SSI is the best predicted complication and is well-predicted across both autologous and prosthetic reconstruction types.

Minimal residual disease (MRD) diagnostics are implemented in most clinical protocols for patients with acute lymphoblastic leukaemia (ALL) and are mostly performed using rearranged immunoglobulin (IG) and/or T-cell receptor (TR) gene rearrangements as molecular polymerase chain reaction targets. Unfortunately, in 5–10% of patients no or no sensitive IG/TR targets are available, and patients therefore cannot be stratified appropriately. In the present study, we used fusion genes and genomic deletions as alternative MRD targets in these patients, which retrospectively revealed appropriate MDR stratification in 79% of patients with no (sensitive) IG/TR target, and a different risk group stratification in more than half of the cases.

Contains fulltext : 248362.pdf (Publisher’s version ) (Open Access) INTRODUCTION: One-quarter of the relapses in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) occur very early (within 18 months, before completion of treatment), and prognosis in these patients is worse compared to cases that relapse after treatment has ended. METHODS: In this study, we performed a genomic analysis of diagnosis-relapse pairs of 12 children who relapsed very early, followed by a deep-sequencing validation of all identified mutations. In addition, we included one case with a good initial treatment response and on-treatment relapse at the end of upfront therapy. RESULTS: We observed a dynamic clonal evolution in all cases, with relapse almost exclusively originating from a subclone at diagnosis. We identified several driver mutations that may have influenced the outgrowth of a minor clone at diagnosis to become the major clone at relapse. For example, a minimal residual disease (MRD)-based standard-risk patient with ETV6-RUNX1-positive leukemia developed a relapse from a TP53-mutated subclone after loss of the wildtype allele. Furthermore, two patients with TCF3-PBX1-positive leukemia that developed a very early relapse carried E1099K WHSC1 mutations at diagnosis, a hotspot mutation that was recurrently encountered in other very early TCF3-PBX1-positive leukemia relapses as well. In addition to alterations in known relapse drivers, we found two cases with truncating mutations in the cohesin gene RAD21. CONCLUSION: Comprehensive genomic characterization of diagnosis-relapse pairs shows that very early relapses in BCP-ALL frequently arise from minor subclones at diagnosis. A detailed understanding of the therapeutic pressure driving these events may aid the development of improved therapies.

Background WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare contiguous gene deletion syndrome with a 45% to 60% risk of developing Wilms tumor (WT). Currently, surveillance and treatment recommendations are based on limited evidence. Methods Clinical characteristics, treatments, and outcomes were analyzed for patients with WAGR and WT/nephroblastomatosis who were identified through International Society of Pediatric Oncology Renal Tumor Study Group (SIOP‐RTSG) registries and the SIOP‐RTSG network (1989‐2019). Events were defined as relapse, metachronous tumors, or death. Results Forty‐three patients were identified. The median age at WT/nephroblastomatosis diagnosis was 22 months (range, 6‐44 months). The overall stage was available for 40 patients, including 15 (37.5%) with bilateral disease and none with metastatic disease. Histology was available for 42 patients; 6 nephroblastomatosis without further WT and 36 WT, including 19 stromal WT (52.8%), 12 mixed WT (33.3%), 1 regressive WT (2.8%) and 2 other/indeterminable WT (5.6%). Blastemal type WT occurred in 2 patients (5.6%) after prolonged treatment for nephroblastomatosis; anaplasia was not reported. Nephrogenic rests were present in 78.9%. Among patients with WT, the 5‐year event‐free survival rate was 84.3% (95% confidence interval, 72.4%‐98.1%), and the overall survival rate was 91.2% (95% confidence interval, 82.1%‐100%). Events (n = 6) did not include relapse, but contralateral tumor development (n = 3) occurred up to 7 years after the initial diagnosis, and 3 deaths were related to hepatotoxicity (n = 2) and obstructive ileus (n = 1). Conclusions Patients with WAGR have a high rate of bilateral disease and no metastatic or anaplastic tumors. Although they can be treated according to existing WT protocols, intensive monitoring of toxicity and surveillance of the remaining kidney(s) are advised. Lay Summary WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare genetic condition with an increased risk of developing Wilms tumor.In this study, 43 patients with WAGR and Wilms tumor (or Wilms tumor precursor lesions/nephroblastomatosis) were identified through the international registry of the International Society of Pediatric Oncology Renal Tumor Study Group (SIOP‐RTSG) and the SIOP‐RTSG network. In many patients (37.5%), both kidneys were affected. Disease spread to other organs (metastases) did not occur.Overall, this study demonstrates that patients with WAGR syndrome and Wilms tumor can be treated according to existing protocols. However, intensive monitoring of treatment complications and surveillance of the remaining kidney(s) are advised., Patients with WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) and Wilms tumor/nephroblastomatosis, identified through the International Society of Pediatric Oncology Renal Tumor Study Group registries and network, have a high rate of bilateral disease and no metastatic or anaplastic tumors. Although they can be treated according to existing Wilms tumor protocols, intensive monitoring of toxicity and surveillance of the remaining kidney(s) are advised.

Introduction The aim of this study was to report a long-term follow-up of patients treated with autologous matrix-induced chondrogenesis (AMIC) for full-thickness chondral and osteochondral defects of the femoral condyle or patella combined with the correction of lower limb malalignment or patellar tracking if indicated. Methods Thirty-three patients (thirty-four knees) were treated surgically for chondral and osteochondral cartilage defects of the knee joint. Regarding the origin of the lesion, patients were divided into three groups. Chondral lesions were observed in the patella (cP group) in fifteen patients, whereas eight patients demonstrated a femoral condylar location (cF group). Eleven patients presented with osteochondritis dissecans of the femur (ocF group). Associated procedures involving realignment of the patella, osteotomy around the knee, or cancellous bone grafting were performed when necessary. The mean size of the lesions was 2.8 ± 1.6 cm2, and the mean patient age was 37.1 ± 11.9 years. To evaluate the clinical outcomes, the Lysholm score and the VAS pain score were imposed, as well as the reoperation rate. Results After an average of 9.3 ± 1 years, follow-up was completed in 79% of the patients. Two patients from the cohort received a total knee prosthesis. The primary outcome measures (Lysolm and VAS pain) at 9-year follow-up were 85 ± 13 for the Lysholm score and 1.9 ± 1.6 for the VAS score in the entire analyzed population. Compared to the preoperative values (Lysholm 56 ± 19, VAS 5.8 ± 2.4) and the 2-year results (Lysholm 85 ± 16, VAS 2.0 ± 2.1), there was significant improvement in the first 2 years after intervention and a stable course in the long-term observation. The same was observed in the cP and ocF subgroups, whereas patients of the cF group showed even further improvement. Conclusions AMIC showed durable results in aligned knees. The favorable outcome was maintained after an average of 9 years when malalignment of the lower limb and patellar maltracking were corrected. Such data are particularly encouraging for young adult patients who may benefit from a procedure that circumvents early arthroplasty.

The design of colloidal nanostructures as surface-enhanced Raman scattering (SERS) substrates requires control over both structural and optical characteristics. A widespread expectation is that the SERS efficiency depends crucially on whether the plasmonic excitation matches the exciting laser wavelength. However, also the balance between radiative (scattering) and non-radiative (absorbing) properties plays a major role, regarding both the efficiency of near field enhancement and the experimentally observed signal intensity. We present a study of the influence of mode-excitation matching and extinction characteristics for core/satellite superstructures, comprising gold nanotriangles decorated with small gold nanospheres. The variation of the core size and aspect ratio allowed tuning the main coupled mode between 700 and 800 nm, from off-resonant through resonant at 785 nm, as well as tuning extinction contributions, from dominantly absorbing to dominantly scattering. We observed additional gains of 1-2 orders of magnitude in signal enhancement, which were correlated to core size and diffuse optical properties. Our findings indicate a competition between SERS enhancement and increased scattering losses in larger assemblies. Thus, a balance of optical parameters is required for efficient SERS and the development of assemblies as advanced sensing devices.

In this paper, we propose an approach for coupling a power network dispatch model, which is part of a long-term multi-energy model, with Wardrop or Mean-Field-Game (MFG) equilibrium models that represent the demand response of a large population of small “prosumers” connected at the various nodes of the electricity network. In a deterministic setting, the problem is akin to an optimization problem with equilibrium constraints taking the form of variational inequalities or nonlinear complementarity conditions. In a stochastic setting, the problem is formulated as a robust optimization with uncertainty sets informed by the probability distributions resulting from an MFG equilibrium solution. Preliminary numerical experimentations, using heuristics mimicking standard price adjustment techniques, are presented for both the deterministic and stochastic cases.

Contains fulltext : 248373.pdf (Publisher’s version ) (Open Access)

Survival of unilateral Wilms tumors (WTs) is exceeding 90%, whereas bilateral WTs have an inferior outcome. We evaluated all Dutch patients with bilateral kidney tumors, treated in the first five years of national centralization and reviewed relevant literature. We identified 24 patients in our center (2015–2020), 23 patients had WT/nephroblastomatosis and one renal cell carcinoma. Patients were treated according to SIOP-RTSG protocols. Chemotherapy response was observed in 26/34 WTs. Nephroblastomatosis lesions were stable (n = 7) or showed response (n = 18). Nephron-sparing surgery was performed in 11/22 patients undergoing surgery (n = 2 kidneys positive margins). Local stage in 20 patients with ≥1 WT revealed stage I (n = 7), II (n = 4) and III (n = 9). Histology was intermediate risk in 15 patients and high risk in 5. Three patients developed a WT in a treated nephroblastomatosis lesion. Two of 24 patients died following toxicity and renal failure, i.e., respectively dialysis-related invasive fungal infection and septic shock. Genetic predisposition was confirmed in 18/24 patients. Our literature review revealed that knowledge is scarce on bilateral renal tumor patients with metastases and that radiotherapy seems important for local stage III patients. Bilateral renal tumors are a therapeutic challenge. We describe management and outcome in a national expert center and summarized available literature, serving as baseline for further improvement of care.

We report on the irradiation of gold rod–sphere assemblies with ultrashort laser pulses, producing structures that are very difficult to obtain by other methods. The optical response of these assemblies displays several peaks arising from the interaction of the plasmon modes of the individual particles, offering thus great flexibility to control the energy deposited on the individual particles. Judicious selection of the wavelength and fluence of the laser pulses allow fine control over the changes produced: the particles can be melted, welded and/or the organic links cleaved. In this way, it is possible to generate structures “à la carte” with a degree of control unmatched by other synthetic protocols. The method is exemplified with gold nanoparticles, but it can be easily implemented on particles composed of different metals, widening considerably the range of possibilities. The final structures are excellent candidates for surface-enhanced spectroscopies or plasmonic photothermal therapy as they have a very intense electric field located outside the structure, not in the gaps.

BackgroundTo assess the prognostic value of early echocardiographic indices of right ventricular function and vasoactive peptides for prediction of bronchopulmonary dysplasia (BPD) or death in very preterm infants.MethodsProspective study involving 294 very preterm infants (median [IQR] gestational age 28.4 [26.4–30.4] weeks, birth weight 1065 [800–1380] g), of whom 57 developed BPD (oxygen supplementation at 36 weeks postmenstrual age) and 10 died. Tricuspid annular plane systolic excursion (TAPSE), right ventricular index of myocardial performance (RIMP), plasma concentrations of mid-regional pro-atrial natriuretic peptide (MR-proANP) and C-terminal pro-endothelin-1 (CT-proET1) were measured on day 7 of life.ResultsRIMP was significantly increased (median [IQR] 0.3 [0.23–0.38] vs 0.22 [0.15–0.29]), TAPSE decreased (median [IQR] 5.0 [5.0–6.0] vs 6.0 [5.4–7.0] mm), MR-proANP increased (median [IQR] 784 [540–936] vs 353 [247–625] pmol/L), and CT-proET1 increased (median [IQR] 249 [190–345] vs 199 [158–284] pmol/L) in infants who developed BPD or died, as compared to controls. All variables showed significant but weak correlations with each other (rS-0.182 to 0.359) and predicted BPD/death with similar accuracy (areas under receiver operator characteristic curves 0.62 to 0.77). Multiple regression revealed only RIMP and birth weight as independent predictors of BPD or death.ConclusionsVasoactive peptide concentrations and echocardiographic assessment employing standardized measures, notably RIMP, on day 7 of life are useful to identify preterm infants at increased risk for BPD or death.

BACKGROUND: CNS directed chemotherapy (chemo) reduces the risk of CNS relapse of ALL, but the optimal way to measure baseline CNS involvement is controversial. Baseline CSF testing can provide risk stratification and often dictates CNS prophylaxis (ppx) during initial treatment. Despite advances, up to 10% of adults still suffer CNS relapse (Blood 2008;112:1646, Cancer 2014;120:3660). Testing typically focuses on conventional cytospin (CC) of CSF, but CC is limited by interobserver variability and insensitivity (Blood 2014;124:3799). Alternatively, MFC is more sensitive (ASH 2018, #658). A previous study in children with ALL found leukemia detection in the CNS by CC or MFC at diagnosis to be associated with an increased risk of both isolated bone marrow and any CNS relapse (ASH 2018, #657). To our knowledge, this use of MFC has not specifically been studied in hyperCVAD, a commonly used chemotherapy regimen for the initial treatment of adult ALL. We hypothesized that baseline lymphoblast detection in the CSF by MFC is predictive of CNS relapse. METHODS: We included data collected from 11/6/07 to 6/22/20. Patients (pts) ≥18 years old who received ≥4 cycles (equivalent of cycle 2B) of hyperCVAD as first-line therapy were eligible. Pts must have had MFC done on CSF at baseline. Pts with mixed phenotype or insufficient follow-up data were excluded. CNS ppx with hyperCVAD historically uses intra-CSF (ie, intrathecal or intraventricular) methotrexate 12 mg on day 2 and cytarabine 100 mg on day 8 of each cycle for 6-12 doses without cranial radiation, though all patients were treated per physician discretion. CC and MFC results were taken from clinical reports and verified by an independent hematopathologist (Dr. Cherian). Baseline CSF positivity (CSF+) and negativity (CSF-) were defined by MFC, with any percentage of lymphoblasts considered CSF+. COG definitions of CNS status by CC were also used (J Clin Oncol 2016;34:2380). Univariate Cox models evaluated associations to CNS relapse. Kaplan-Meier curves were used to estimate the probabilities of overall survival (OS) and cumulative incidence of CNS relapse. RESULTS: We identified 92 eligible pts. Disease and treatment characteristics are summarized in Table 1, and results of initial CSF testing are shown in Table 2. Twenty-one pts were CSF+ by MFC at baseline: by CC, 6 of these were positive, 6 were negative, 7 were equivocal (ie, morphologic review was unable to rule out blasts), and 2 did not have baseline CC. None were positive by CC but negative by MFC. Eight of 29 (38%) with circulating blasts had a traumatic (>10 RBC/uL of CSF) first lumbar puncture (LP). Of these 8, 4 (50%) were CSF+. Five (5%) pts had an Ommaya reservoir placed during treatment. Pts received a median of 8 doses of intra-CSF chemo (range, 5-52). All but 7 pts (8%) received a combination of methotrexate and cytarabine like above. Twenty CSF+ pts (95%) achieved CSF- after a median of 1 dose of intra-CSF chemo (range, 1-5). Out of the 71 CSF- pts, none became CSF+ during initial treatment despite being tested a median of 5 times (range, 2-10). Eight pts (9%) had CNS relapse (3 isolated, 5 concurrent medullary relapse). Comparisons between baseline CSF testing, intra-CSF treatment, and CNS relapse are shown in Table 2. CSF+ pts received significantly greater doses of intra-CSF chemo. Of the 21 CSF+ pts, 5 (24%) had CNS relapse (2 isolated, 3 concurrent), and out of the 71 CSF- pts, 3 (4%) had CNS relapse (1 isolated, 2 concurrent; p=0.014). Among univariate models of CSF+ vs -, traumatic LP vs not, B vs T lineage, LDH, and WBC, only CSF+ was significantly associated with CNS relapse (hazard ratio 4.8, 95% confidence interval [CI] 1.2-20, p=0.031). Estimated 3-year cumulative incidence of CNS relapse for CSF+ was 15% vs 3.3% for CSF- (Figure 1). Median OS for the whole cohort was not reached, with estimated 3-year OS of 74% (95% CI, 65%-84%). CONCLUSIONS: MFC of CSF is more predictive of CNS relapse risk than CC in the context of front-line hyperCVAD, questioning the use of CC if MFC is performed. Further, CNS relapses were significantly more frequent when CSF+ despite administration of significantly more intra-CSF chemo. Traumatic LP per se did not increase risk of CNS relapse if CSF- by MFC. Surveillance during treatment by MFC in CSF- pts identified no cases of occult CNS relapse, arguing against this routine practice. Future studies should consider incorporating MFC of CSF into risk-adapted CNS-directed treatment strategies. Disclosures Shustov: Seattle Genetics: Research Funding. Becker:Accordant Health Services/Caremark: Membership on an entity's Board of Directors or advisory committees; Cardiff Oncology: Research Funding; SecuraBio: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; JW Pharmaceutical: Research Funding; Glycomimetics: Research Funding; Abbvie: Research Funding; Bristol Myers Squibb: Research Funding; Invivoscribe: Research Funding. Oehler:Takeda: Consultancy; BMS: Consultancy; Pfizer, Inc: Research Funding. Halpern:Bayer: Other; Novartis: Other; Jazz Pharmaceuticals: Other; Imago BioSciences: Other; Tolero Pharmaceuticals: Research Funding. Walter:Amgen: Consultancy, Research Funding; Arog: Research Funding; Argenx: Consultancy; Aptevo: Consultancy, Research Funding; Amphivena: Current equity holder in publicly-traded company; Agios: Consultancy, Research Funding; StemLine: Research Funding; Selvita: Research Funding; Seattle Genetics: Research Funding; Race Oncology: Consultancy; Pfizer: Consultancy, Research Funding; New Link Genetics: Consultancy; Macrogenics: Research Funding; Kite: Consultancy; Jazz: Consultancy, Research Funding; ImmunoGen: Research Funding; Genentech: Consultancy; Daiichi: Consultancy; Celgene: Consultancy, Research Funding; Boston Biomedical: Consultancy; BiVictriX: Consultancy; BioLineRx: Consultancy, Research Funding; Astellas: Consultancy. Godwin:Pfizer Inc.: Research Funding; Immunogen Inc.: Research Funding. Cassaday:Kite/Gilead: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Current Employment, Current equity holder in publicly-traded company; Amgen: Consultancy, Research Funding; Vanda Pharmaceuticals: Research Funding; Pfizer: Honoraria, Research Funding.

Simple Summary Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary disorders which significantly increase a person’s risk of developing a variety of cancers such as colorectal, endometrial, brain and, for CMMRD also, haematological malignancies. This increased cancer risk is due to inherited mutations in specific types of DNA repair genes, which hampers repair of mispaired or damaged bases during DNA replication. As a consequence, somatic mutations rapidly accumulate and typically include insertions and deletions (indels) in microsatellites that potentially can give rise to neoantigens. These neoantigens open up avenues for neoantigen-targeting immune therapies. Here, we aim to discuss the major obstacles that are encountered in developing such a therapy, including the heterogenous tumour profile of LS and CMMRD patients which challenge the selection of suitable neoantigens and potential resistance to immune checkpoint inhibitor therapy. In addition, we give a perspective on how to overcome the encountered obstacles. Abstract Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary disorders characterised by a highly increased risk of cancer development. This is due to germline aberrations in the mismatch repair (MMR) genes, which results in a high mutational load in tumours of these patients, including insertions and deletions in genes bearing microsatellites. This generates microsatellite instability and cause reading frameshifts in coding regions that could lead to the generation of neoantigens and opens up avenues for neoantigen targeting immune therapies prophylactically and therapeutically. However, major obstacles need to be overcome, such as the heterogeneity in tumour formation within and between LS and CMMRD patients, which results in considerable variability in the genes targeted by mutations, hence challenging the choice of suitable neoantigens. The machine-learning methods such as NetMHC and MHCflurry that predict neoantigen- human leukocyte antigen (HLA) binding affinity provide little information on other aspects of neoantigen presentation. Immune escape mechanisms that allow MMR-deficient cells to evade surveillance combined with the resistance to immune checkpoint therapy make the neoantigen targeting regimen challenging. Studies to delineate shared neoantigen profiles across patient cohorts, precise HLA binding algorithms, additional therapies to counter immune evasion and evaluation of biomarkers that predict the response of these patients to immune checkpoint therapy are warranted.

Increasing use of genomic sequencing enables standardized screening of all childhood cancer predisposition syndromes (CPS) in children with cancer. Gene panels currently used often include adult-onset CPS genes and genes without substantial evidence linking them to cancer predisposition. We have developed criteria to select genes relevant for childhood-onset CPS and assembled a gene panel for use in children with cancer. We applied our criteria to 381 candidate genes, which were selected through two in-house panels (n = 338), a literature search (n = 39), and by assessing two Genomics England’s PanelApp panels (n = 4). We developed evaluation criteria that determined a gene’s eligibility for inclusion on a childhood-onset CPS gene panel. These criteria assessed (1) relevance in childhood cancer by a minimum of five childhood cancer patients reported carrying a pathogenic variant in the gene and (2) evidence supporting a causal relation between variants in this gene and cancer development. 138 genes fulfilled the criteria. In this study we have developed criteria to compile a childhood cancer predisposition gene panel which might ultimately be used in a clinical setting, regardless of the specific type of childhood cancer. This panel will be evaluated in a prospective study. The panel is available on (pediatric-cancer-predisposition-genepanel.nl) and will be regularly updated. Supplementary Information The online version contains supplementary material available at 10.1007/s10689-021-00254-0.

Background Bronchopulmonary dysplasia (BPD) is a major complication in preterm infants Methods This was a prospective, two-center, observational cohort study. MR-proANP and CT-proET-1 were measured at day 7 (±2) of life. Associations with duration of supplemental oxygen and the composite outcome of moderate or severe BPD or death (BPD/death) were investigated. Results Two hundred and twenty-nine infants p p p = 0.015) compared to infants without BPD/death. Levels of both biomarkers were significantly associated with BPD/death in univariable models but not after adjusting for co-factors. Conclusions MR-proANP and CT-proET-1 are associated with the duration of supplemental oxygen and the composite outcome BPD/death, but their prognostic value does not complement that of clinical risk factors. Impact Plasma levels of MR-proANP and CT-proET-1, measured on day 7 of life (±2 days) are associated in univariable analyses with duration of supplemental oxygen and the combined outcome of BPD or death in VLGA infants. Associations between both biomarkers and respiratory morbidity do not persist in multivariable models, in particular when gestational age is included. MR-proANP and CT-proET-1 have limited additional value to predict respiratory morbidity in VLGA infants compared to clinical parameters.

Water is imperative in the regular day to day existence of the human race. Household people use water to sustain life. Nowadays, household people excessively use water without knowing how much water do they already consume in real-time and are unaware on which faucet in the household has the highest water consumption. With the use of the internet of things (IoT) platform with visual analytics (VA), a real-time water consumption monitoring system has been developed for household and commercialized building applications. In order to get the water consumption data, a Hall Effect water flow sensor is attached to every faucet, which is then processed by a NodeMCU, then pushed to the Heroku cloud database. A Liquid Crystal Display (LCD) alphanumeric screen displays the total volume consumed and the real-time water flow rate for each faucet. To further visualize the water consumption data, a comprehensible chart report about the overall household water consumption from the cloud database can be accessed through a web browser or a mobile device. To achieve an accurate water flow measurement, an initial calibration is being performed for every sensor in the faucet. A test was conducted to determine how accurate the system is in monitoring the correct water consumption. Ten trials of filling up a 10-liter bottle using one faucet, two 10-liter bottles using two faucets, and three 10-liter bottles using three faucets at a time was conducted. The study came up with an overall average accuracy of 99.38%. The study concluded that the developed IoT system can make an accurate water consumption monitoring and can also identify which faucet has the highest consumption using visual analytics.

Acute respiratory tract infections (ARI) in infancy have been implicated in the development of chronic respiratory disease, but the complex interplay between viruses, bacteria and host is not completely understood. We aimed to prospectively determine whether nasal microbiota changes occur between the onset of the first symptomatic ARI in the first year of life and 3 weeks later, and to explore possible associations with the duration of respiratory symptoms, as well as with host, environmental and viral factors. Nasal microbiota of 167 infants were determined at both time-points by 16S ribosomal RNA-encoding gene PCR amplification and subsequent pyrosequencing. Infants were clustered based on their nasal microbiota using hierarchical clustering methods at both time-points. We identified five dominant infant clusters with distinct microbiota at the onset of ARI but only three clusters after 3 weeks. In these three clusters, symptom persistence was overrepresented in the Streptococcaceae-dominated cluster and underrepresented in the cluster dominated by “Others” (p, Nasal microbiota in infants is associated with symptom persistence after acute symptomatic respiratory infections. http://ow.ly/3Mhh30mC1wJ

This paper studies a dynamic collective choice model in the presence of an advertiser, where a large number of consumers are choosing between two alternatives. Their choices are influenced by the group’s aggregate choice and an advertising effect. The latter is produced by an advertiser making investments to convince as many consumers as possible to choose a specific alternative. In schools, for example, teenagers’ decisions to smoke are considerably affected by their peers’ decisions, as well as the ministry of health campaigns against smoking. We model the problem as a Stackelberg dynamic game, where the advertiser makes its investment decision first, and then the consumers choose one of the alternatives. On the methodological side, we use the theory of mean field games to solve the game for a continuum of consumers. This allows us to describe the consumers’ individual and aggregate behaviors, and the advertiser’s optimal investment strategies. When the consumers have sufficiently diverse a priori opinions toward the alternatives, we show that a unique Nash equilibrium exists between them, which predicts the distribution of choices over the alternatives, and the advertiser can always make optimal investments. For a certain uniform distribution of a priori opinions, we give an explicit form of the advertiser’s optimal investment strategy and of the consumers’ optimal choices.

Situated analytics (SA), a combination of augmented reality and visual analytics, is a potential tool in enhancing user understanding of information. This study created a mobile application (app) named FoodGo, which utilizes SA to present product information in mobile devices, to help consumers in making a food choice in a grocery shopping scenario. FoodGo was designed in such a way that users just need to scan the barcode of a food product using the smartphone’s camera and the helpful food information will then be augmented in the smartphone display using the concept of situated analytics. An iterative process of design analysis, prototype development, and user interface evaluation was used in designing and developing the mobile app prototype. The iterative process was limited to three iterations only and the data gathered in each iteration was used to improve the mobile app in the succeeding iterations. After the iteration cycles, the final version of the Android FoodGo mobile app was developed and was ensured that all the components, which includes the barcode scanning and the cloud database, were working properly. The effectiveness of using the mobile app in helping consumers make a healthier food choice was assessed in a mock-up grocery shopping environment. The result indicated that using FoodGo significantly improves the success rate of users to select a healthier food product. Further improvements for the FoodGo mobile app include putting a tutorial on how to use the mobile app when opened for the first time and having an option to input special health conditions such as diabetes for a more personalized way of informing the user about the food products.

It is now well established that germline genomic aberrations can underlie high-penetrant familial polyposis and colorectal cancer syndromes, but a genetic cause has not yet been found for the major proportion of patients with polyposis. Since next-generation sequencing has become widely accessible, several novel, but rare, high-penetrant risk factors for adenomatous polyposis have been identified, all operating in pathways responsible for genomic maintenance and DNA repair. One of these is the base excision repair pathway. In addition to the well-established role of the DNA glycosylase gene MUTYH, biallelic mutations in which predispose to MUTYH-associated polyposis, a second DNA glycosylase gene, NTHL1, has recently been associated with adenomatous polyposis and a high colorectal cancer risk. Both recessive polyposis syndromes are associated with increased risks for several other cancer types as well, but the spectrum of benign and malignant tumours in individuals with biallelic NTHL1 mutations was shown to be broader; hence the name NTHL1-associated tumour syndrome. Colorectal tumours encountered in patients with these syndromes show unique, clearly distinct mutational signatures that may facilitate the identification of these syndromes. On the basis of the prevalence of pathogenic MUTYH and NTHL1 variants in the normal population, we estimate that the frequency of the novel NTHL1-associated tumour syndrome is five times lower than that of MUTYH-associated polyposis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Networked control systems must use communication links between control hubs and distributed components, possibly both to observe component states, and to send control commands. We consider a model of a CDMA based communication and control system where the power sent from the components to the base station, acting as the control hub, is proportional to their (scalar) state, and in turn, the base station sends back the required control commands to the components. The systems are linear, and commands are constrained to be linear, possibly time varying feedback laws on current and a limited set of recent measurements. However, the individual measurements as decoded by the base station include interference terms from the set of all other components, and this inadvertently creates an interference induced game situation. The consequence is that controls have dual effects: they steer individual systems, but they can also help create additional interference. We propose an algorithm which accounts for a combination of control and estimation costs to compute symmetric Nash equilibria if they exist.

The histone-lysine-N-methyltransferase 2A (KMT2A) gene (formerly known as mixed-lineage leukemia (MLL)) plays an essential role in regulating gene expression including homeobox (HOX) and MEIS1 genes. In 5-10% of AML cases, specific KMT2A gene perturbations can occur which result in an aggressive and poor prognostic group of blood cancers. The KMT2A complex also appears to play a central role in the epigenetic dysregulation in AMLs with co-mutations such as NPM1, IDH1/2, EZH2, and DNMT3A. Therefore, there is strong rationale for targeting these AML subsets which may be exquisitely sensitive to inhibition of the menin-KMT2A chromatin complex. KO-539 is a novel, once daily, oral investigational drug candidate targeting the menin-KMT2A protein-protein interaction. KOMET-001 (NCT04067336) is an ongoing Phase 1/2A open-label study evaluating KO-539 in adult patients (pts) with relapsed and/or refractory AML agnostic to oncogenic mutational type. The Phase 1 dose-escalation objectives are to assess safety and tolerability, characterize the pharmacokinetics (PK), and determine a recommended Phase 2 dose. The Phase 2A dose expansion portion will assess anti-leukemic activity, PK, safety and tolerability in select genetic subtypes of AML. Preclinically, the drug is shown to be highly protein bound (>99%) across animal species. Using physiologically-based PK (PBPK) modeling, the estimated human efficacious dose was estimated to be 600 mg po qd. As of data cutoff on August 10, 2020, 6 pts with relapsed and/or refractory AML have been enrolled in the trial. Dose escalation began with single pt cohorts at 50 mg po qd in 28 day cycles and has proceeded through to 200 mg dosing cohorts. An expansion of 3 pts at 200 mg was initiated to better characterize the PK and exposure of KO-539. To date, 3 enrolled pts have been studied for safety and have not experienced any dose-limiting toxicities (DLTs) within the 28 day DLT-assessment window. Grade 3 (G3) or higher drug related adverse events have included G3 tumor lysis syndrome (TLS) at 50 mg and a G3 embolic event at 100 mg. KO-539 has been well tolerated with no dose interruptions or discontinuations due to drug related adverse events. There were no treatment-related deaths, and two pts discontinued treatment due to disease progression. Peak drug concentrations were attained between 2-3 hours after daily oral dosing with an elimination half-life of greater than 24 hours. KO-539 has demonstrated evidence of biologic activity in pts in the first 3 dose levels treated to date. The 50 mg pt with a KMT2A-r and the 200 mg pt with a p53 mutation and PICALM-AF10 fusion exhibited evidence of tumor lysis syndrome and markedly decreased hydroxyurea requirements with blood count stabilization, respectively. A third pt (100 mg dose level) with SETD2 and RUNX1 co-mutations achieved a complete remission with confirmed negative MRD by flow cytometry after two cycles of therapy and continues on treatment. The biologic activity of KO-539 at lower doses may be explained by inhibition of the CYP3A4 enzyme by concomitantly administered azole antifungals. KO-539 is metabolized into at least two metabolites with comparable activity to KO-539; total drug concentrations (i.e., KO-539 plus active metabolites) exhibited a dose-dependent increase. Although KO-539 is a CYP3A4 substrate, preclinical data suggest both KO-539 and its metabolites act as inhibitors, potentially providing an advantage in overcoming drug resistance attributable to CYP3A4 metabolism by bone marrow stroma. The physiology of the bone marrow sinusoids also allows both unbound and protein-bound drug to reach the sites of leukemic involvement. The high level of protein binding may therefore provide an opportunity for organ-specific targeted action while possibly limiting off target effects. The potential advantage associated with the CYP3A4 inhibitory characteristics of KO-539 to overcome drug-resistance in the bone marrow stroma also continues to be investigated. In conclusion, the early biologic activity of KO-539 in relapsed AML is encouraging, and its unique PK characteristics may be advantageous for clinical benefit. In addition to the above, any updated safety, PK, and efficacy data will be presented at the time of the conference. Disclosures Wang: Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; Genentech: Consultancy; Pfizer: Speakers Bureau; Stemline: Speakers Bureau; PTC Therapeutics: Consultancy; Macrogenics: Consultancy; Astellas: Consultancy. Altman:BioSight: Other: No payment but was reimbursed for travel , Research Funding; Kura Oncology: Other: Scientific Advisory Board - no payment accepted, Research Funding; Daiichi Sankyo: Other: Advisory Board - no payment but was reimbursed for travel; Bristol-Myers Squibb: Consultancy; Boehringer Ingelheim: Research Funding; Celgene: Research Funding; Kartos: Research Funding; Fujifilm: Research Funding; France Foundation: Consultancy; PrIME Oncology: Consultancy; Novartis: Consultancy; Theradex: Other: Advisory Board; Agios: Other: advisory board, Research Funding; Glycomimetics: Other: Data safety and monitoring committee; Janssen: Consultancy; ASH: Consultancy; Amphivena: Research Funding; Immune Pharmaceuticals: Consultancy; Syros: Consultancy; Amgen: Research Funding; ImmunoGen: Research Funding; Genentech: Research Funding; Aprea: Research Funding; AbbVie: Other: advisory board, Research Funding; Astellas: Other: Advisory Board, Speaker (no payment), Steering Committee (no payment), Research Funding; Cancer Expert Now: Consultancy; PeerView: Consultancy. Pettit:PharmaEssentia: Other: advisory board; Kura Oncology: Other: advisory board; CTI Biopharma: Other: advisory board. Walter:Kite: Consultancy; Race Oncology: Consultancy; Pfizer: Consultancy, Research Funding; Macrogenics: Research Funding; New Link Genetics: Consultancy; Selvita: Research Funding; Seattle Genetics: Research Funding; StemLine: Research Funding; Agios: Consultancy, Research Funding; Aptevo: Consultancy, Research Funding; Daiichi: Consultancy; Celgene: Consultancy, Research Funding; Boston Biomedical: Consultancy; BiVictriX: Consultancy; BioLineRx: Consultancy, Research Funding; Astellas: Consultancy; Jazz: Consultancy, Research Funding; ImmunoGen: Research Funding; Genentech: Consultancy; Arog: Research Funding; Argenx: Consultancy; Amphivena: Current equity holder in publicly-traded company; Amgen: Consultancy, Research Funding. Fenaux:Novartis: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Burrows:Kura Oncology: Current Employment, Current equity holder in publicly-traded company. Tomkinson:Kura Oncology: Current Employment. Martell:Kura Oncology: Current Employment, Current equity holder in publicly-traded company. Fathi:Daiichi Sankyo: Consultancy; Amphivena: Consultancy, Honoraria; Astellas: Consultancy; Celgene: Consultancy, Research Funding; PTC Therapeutics: Consultancy; TrovaGene: Consultancy; Takeda: Consultancy; Kura: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy; Agios: Consultancy, Research Funding; AbbVie: Consultancy; Novartis: Consultancy; Kite: Consultancy, Honoraria; NewLink Genetics: Consultancy, Honoraria; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Blue Print Oncology: Consultancy; Boston Biomedical: Consultancy; Forty Seven: Consultancy; Jazz: Consultancy, Honoraria.

BACKGROUND. SEL24/MEN1703 is a first-in-class, orally available, dual PIM/FLT3 kinase inhibitor investigated in unselected AML patients in the First-in-Human, Dose Escalation (DE) and Cohort Expansion (CE) DIAMOND trial (clinicaltrials.gov identifier: NCT03008187). The study has completed the DE part showing an acceptable safety profile up to the recommended dose (RD), with initial evidence of single agent efficacy1. Preclinical studies conducted in vitro - using a panel of 26 AML cell lines harboring different genetic alterations - and in vivo - in xenograft mouse model bearing MOLM-16 cell line - showed a direct correlation between the activity of SEL24/MEN1703 and the inhibition of S6 phosphorylation (pS6) protein, a downstream target of PIM/FLT3 signaling pathway. AIM. To assess the degree of target engagement and its preliminary correlation with the anti-leukemic effect of SEL24/MEN1703 in samples collected from patients enrolled in the DE part of DIAMOND trial. METHODS. S6 phosphorylation has been longitudinally monitored in the DIAMOND study through an optimized assay for multiparametric analysis of phospho-protein activation. The assay allows a quantitative assessment of pS6 at single cell level among blast cells as well as the identification of blast subpopulations in both peripheral blood (PB) and bone marrow (BM). Blast counts were monitored to assess whether the target engagement did translate into blast count reduction. RESULTS. Two cohorts of patients, treated at 100 mg (one dose level below RD) and 125 mg (RD) were analyzed, for a total of n=9 evaluable patients on PB and n=7 on BM. At screening we observed a heterogeneous positivity for pS6 marker in blast cells (range: 1%-53 %) both in PB and in BM, consistent with the unselected AML patient population recruited in the trial. Overall, 7/9 PB and 4/7 BM samples showed pS6 inhibition in blast cells at the end of the Cycle 1 in comparison with screening (range: 70%-94% and 26%-76% in PB and BM, respectively) (Figure 1). In the cohort treated at 100 mg such strong pathway inhibition did not correlate with blast count reduction. Interestingly, in samples from a patient treated at 125 mg who harbored the highest burden of pS6+ blast cells (>25%), a correlation between pathway inhibition and blast count reduction was observed suggesting that a higher burden of blasts with activated pS6 might be more sensitive to the inhibition of the pathway (Figure 1). CONCLUSIONS. The longitudinal PD assessment through the modulation of pS6 activation by flow cytometry confirmed that meaningful target engagement was achieved, both in PB and BM, in patients treated with SEL24/MEN1703 at 100 and 125 mg. Preliminary data suggest that the FLT3/PIM pathway inhibition might be associated with blast count reduction, particularly in case of high baseline activation of pS6. Longitudinal monitoring of PD will be continued in the CE part of DIAMOND trial. REFERENCES. 1. Solomon et al, EHA 2020 Disclosures Tomirotti: Menarini Ricerche: Current Employment. Bellarosa:Menarini Ricerche: Current Employment. Walter:Genentech: Consultancy; Selvita: Research Funding; StemLine: Research Funding; Daiichi: Consultancy; Celgene: Consultancy, Research Funding; Boston Biomedical: Consultancy; BiVictriX: Consultancy; BioLineRx: Consultancy, Research Funding; Astellas: Consultancy; Arog: Research Funding; Argenx: Consultancy; Aptevo: Consultancy, Research Funding; Amphivena: Current equity holder in publicly-traded company; Amgen: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Seattle Genetics: Research Funding; Race Oncology: Consultancy; Pfizer: Consultancy, Research Funding; New Link Genetics: Consultancy; Macrogenics: Research Funding; Kite: Consultancy; Jazz: Consultancy, Research Funding; ImmunoGen: Research Funding. Ravandi:Abbvie: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Brzózka:Ryvu Therapeutics: Current Employment. Baldini:Menarini Ricerche: Current Employment. Salerno:Menarini Richerce: Current Employment. Binaschi:Menarini Ricerche: Current Employment. Laurent:Menarini Ricerche: Current Employment. Pellacani:Menarini Ricerche: Current Employment.

Introduction Since 2017, therapeutic options for acute myeloid leukemia (AML) have expanded rapidly with the FDA approval of 8 new agents. This has provided new therapeutic options for both patients and healthcare providers (HCPs), but it has also introduced new challenges, including the selection of the optimal agent(s) and sequencing strategies that optimize patient benefit and minimize toxicity. To help address these challenges, we developed an online AML decision support tool designed to provide HCPs with expert guidance on optimal treatment (Tx) for personalized patient scenarios. Methods In February 2019, a panel of 5 experts in AML provided Tx recommendations for 330 distinct patient scenarios in the settings of newly diagnosed (ND; n = 150) and relapsed/refractory (RR; n = 180) disease. These scenarios were defined by patient and disease characteristics identified by the experts as important when making Tx choices and include disease setting, patient age and fitness, previous MDS or MPN, cytogenetic data, presence of specific biomarkers, and previous therapy. To use the tool, HCPs are prompted to select defined patient/disease characteristics from provided options and then are asked to provide their Tx choice for that specific patient scenario. After this, they are shown the recommendations of the 5 experts based on those same characteristics and are asked to indicate the impact of the expert recommendations on their planned Tx approach. Results From June 2019 to July 2020, a total of 417 unique HCPs used the AML tool, 85% specializing in hematology and/or oncology and 59% being physicians. Two thirds of the HCPs reported treating ≤ 10 patients with AML each month. Tool users entered 934 patient case scenarios-748 (80%) ND and 186 (20%) RR cases; 51% of cases that were identified for patient type (actual or hypothetical) represented actual patients in their practices. Overall, the Tx selections by HCPs agreed with expert choices only 36% of the time for ND fit patients and 33% of the time for ND unfit patients. Most of the entered ND cases focused on fit patients ≤ 75 years of age (n = 535; 72%). For this patient group, the experts recommended primarily 3 Tx options: CPX-351 (29%), 7+3 plus gemtuzumab ozogamicin (22%), and venetoclax + HMA (20%) (Table). Conversely, HCPs selected these top 3 Txs in only 20% of their cases, instead choosing the 7+3 regimen for 33% of their cases, with another 22% uncertain of Tx choice. For the entered ND unfit or > 75 years of age patient scenarios, the disparity in Tx choices continued, with experts selecting a venetoclax regimen in 74% of cases (64% combined with HMA and 10% with LDAC) vs in 33% of HCP cases (Table). Experts also recommended FLT3 and IDH1/2 inhibitor therapies as monotherapy in the upfront setting in unfit patients far more frequently than HCPs (18% vs < 1% of cases). In RR AML patient scenarios, HCP Tx selections again differed considerably from the experts in both the fit population (n = 134) and older, less fit population (n = 52). For example, experts selected targeted therapy for 87% of patients with FLT3 or IDH1/2 mutations in RR AML, yet HCPs only selected targeted agents for 47% of these patient scenarios. In an optional question, among HCPs who initially differed from the expert recommendations (50% of total), 56% planned to change their Tx approach, 28% reported that barriers prevented them from changing their Tx, and 16% remained uncertain about choice of therapy. Conclusions The analysis of data from this online tool found several areas of expert consensus regarding Tx strategies for patients with AML, particularly regarding the use of venetoclax + HMAs for older, less fit patients with ND AML, intensive induction strategies in younger/fit AML patients, and targeted therapies for RR AML patients with FLT3 or IDH1/2 mutations. Overall, practice patterns of community HCPs differed from the experts for the majority of entered cases. The disparity in Tx choices between community HCPs and experts suggests a continued need for education through Tx decision tools such as this as well as other innovative approaches to increase HCP awareness of expert recommendations and best practices in AML. A detailed comparison of expert and user data from the online tool will be presented. Disclosures Ravandi: Macrogenics: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria. Smith:Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Walter:Selvita: Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding; Pfizer: Consultancy, Research Funding; New Link Genetics: Consultancy; Macrogenics: Research Funding; Agios: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Amphivena: Current equity holder in publicly-traded company; Aptevo: Consultancy, Research Funding; Argenx: Consultancy; Arog: Research Funding; Astellas: Consultancy; BioLineRx: Consultancy, Research Funding; BiVictriX: Consultancy; Boston Biomedical: Consultancy; Celgene: Consultancy, Research Funding; Daiichi: Consultancy; Genentech: Consultancy; ImmunoGen: Research Funding; Jazz: Consultancy, Research Funding; Kite: Consultancy; StemLine: Research Funding. Wang:Astellas: Consultancy; Macrogenics: Consultancy; PTC Therapeutics: Consultancy; Stemline: Speakers Bureau; Genentech: Consultancy; Pfizer: Speakers Bureau; Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy. Lancet:Abbvie: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Astellas Pharma: Consultancy; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy. OffLabel Disclosure: In this report of results from a treatment decision support tool for AML, some of the drugs selected by the experts are recommended in off-label applications (eg, IDH1/2 inhibitors ivosidenib and enasidenib in frontline AML therapy).

Background: The persistence of measurable residual disease (MRD) has been shown to correlate with higher rates of relapse and worse survival in several leukemias. Individual studies have similarly suggested that the detection of MRD is associated with inferior outcomes in patients with acute myeloid leukemia (AML) undergoing frontline therapy; however, the optimal use of MRD information to risk stratify patients and inform clinical decision-making has been limited in part by the heterogeneity of these reports. To better understand the relationship between MRD and clinical outcomes in AML, we performed a literature-based meta-analysis of published AML studies reporting the association of MRD with survival outcomes. Methods: We conducted independent searches of PubMed, MEDLINE, and Embase for papers published between January 1, 2000 and October 1, 2018 that included the keywords "AML," "acute myeloid leukemia," or "acute myelogenous leukemia," in combination with the keywords "MRD," "minimal residual disease," or "measurable residual disease." Reviews, non-English articles, and studies only reporting outcomes after hematopoietic stem cell transplantation or those with insufficient description of MRD information were excluded. Study sample size, patient age, median follow-up time, MRD detection method, MRD assessment time point(s), AML subtype, specimen source, and survival outcomes were extracted. Meta-analyses of survival probabilities and hazard ratios (HRs) were performed separately for disease-free survival (DFS) and overall survival (OS) using Bayesian hierarchical modeling. Results: Eighty-one publications reporting on 11,151 patients were included in the meta-analysis (17 studies for OS, 20 studies for DFS, and 44 for both). Both OS and DFS were better for those who achieved MRD negativity (Figure 1). At 5 years, the estimated OS was 68% (95% Bayesian credible interval [CrI], 63%-73%) for the MRD negative group versus 34% (95% CrI, 28%-40%) for the MRD positive group. Similarly, the estimated DFS at 5 years for the MRD negative and MRD positive groups were 64% (95% CrI, 59%-70%) and 25% (95% CrI, 20%-32%), respectively. The relative benefit of achieving MRD negativity was comparable for both OS and DFS (average HR, 0.36; 95% CrI, 0.33-0.39 for OS; average HR, 0.37; 95% CrI, 0.34-0.40 for DFS). Achievement of MRD negativity was associated with superior DFS and OS irrespective of age group (adult or pediatric), MRD assessment time point (induction, during consolidation or after consolidation), AML subgroup (core-binding factor [CBF] or non-CBF), or specimen source (bone marrow or peripheral blood) (Figure 2). While most of the MRD detection methods were able to identify a difference in DFS and OS between groups with MRD negativity versus MRD positivity, the MRD effect using cytogenetics/FISH was not significant (average HR, 0.77; 95% CrI, 0.39-1.56 for OS and average HR, 0.65; 95% CrI, 0.34-1.23 for DFS), possibly due to only 2 studies being included in this subgroup analysis. The effect of MRD on survival was more profound in studies reporting outcomes of CBF AML compared to non-CBF AML, with a posterior probability of 0.999 for OS and 0.997 for DFS. Interestingly, across AML subtypes, peripheral blood assessment of MRD better distinguished MRD-positive and MRD-negative groups as compared to bone marrow assessment of MRD, with a posterior probability of 0.918 for OS and 0.999 for DFS. Multivariate analysis was performed to control for possible confounding factors that might influence the subgroup analyses. Overall, multivariate results were consistent with the univariate results. All subgroups showed DFS and OS benefit to achievement of MRD negativity, with the exception of MRD detection by cytogenetics/FISH. Conclusions: In this large-cohort meta-analysis, achievement of MRD negativity was strongly associated with superior DFS and OS in patients with AML, an association that was observed across ages, disease subtypes, time of assessment, specimen source, and most MRD detection methods. Given the robustness of the association of MRD with long-term outcomes across studies, MRD status may serve as a valuable clinical endpoint that may allow for accelerated evaluation of novel therapies in AML. Disclosures Short: Astellas: Research Funding; Takeda Oncology: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Berry:Berry Consultants LLC.: Other: Co-owner. Walter:StemLine: Research Funding; Selvita: Research Funding; Seattle Genetics: Research Funding; Race Oncology: Consultancy; BioLineRx: Consultancy, Research Funding; Astellas: Consultancy; Arog: Research Funding; Argenx: Consultancy; Aptevo: Consultancy, Research Funding; Amphivena: Current equity holder in publicly-traded company; Amgen: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; ImmunoGen: Research Funding; Genentech: Consultancy; Daiichi: Consultancy; Celgene: Consultancy, Research Funding; Boston Biomedical: Consultancy; BiVictriX: Consultancy; Pfizer: Consultancy, Research Funding; New Link Genetics: Consultancy; Macrogenics: Research Funding; Kite: Consultancy. Kantarjian:Immunogen: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; BioAscend: Honoraria; Delta Fly: Honoraria; Abbvie: Honoraria, Research Funding; Ascentage: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria; Oxford Biomedical: Honoraria; Adaptive biotechnologies: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Aptitute Health: Honoraria; BMS: Research Funding; Jazz: Research Funding. Ravandi:Orsenix: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding.

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is an autosomal dominant syndrome caused by heterozygous pathogenic germline variants in the fumarate hydratase (FH) gene. It is characterized by cutaneous and uterine leiomyomas and an increased risk of developing renal cell carcinoma (RCC), which is usually adult-onset. HLRCC-related RCC tends to be aggressive and can metastasize even when the primary tumor is small. Data on children and adolescents are scarce. Herein, we report two patients from unrelated Dutch families, with HLRCC-related RCC at the ages of 15 and 18 years, and a third patient with an FH mutation and complex renal cysts at the age of 13. Both RCC’s were localized and successfully resected, and careful MRI surveillance was initiated to monitor the renal cysts. One of the patients with RCC subsequently developed an ovarian Leydig cell tumor. A review of the literature identified 10 previously reported cases of HLRCC-related RCC in patients aged younger than 20 years, five of them presenting with metastatic disease. These data emphasize the importance of recognizing HLRCC in young patients to enable early detection of RCC, albeit rare. They support the recommendations from the 2014 consensus guideline, in which genetic testing for FH mutations, and renal MRI surveillance, is advised for HLRCC family members from the age of 8–10 years onwards. Electronic supplementary material The online version of this article (10.1007/s10689-019-00155-3) contains supplementary material, which is available to authorized users.

Background/Aim: Differentiated vulvar intraepithelial neoplasia (dVIN) and lichen sclerosus (LS) can give rise to vulvar squamous cell carcinoma (VSCC), but genetic evidence is currently still limited. We aimed to determine genetic abnormalities in VSCC and backtrack these abnormalities in the dVIN and LS lesions. Materials and Methods: DNA from VSCC and patient-matched dVIN and LS samples of twelve patients was collected. High-resolution genome-wide copy number analysis was performed and subsequently, we sequenced TP53. Results: Copy number alterations were identified in all VSCC samples. One dVIN lesion presented with three copy number alterations that were preserved in the paired VSCC sample. Targeted sequencing of TP53 identified mutations in five VSCCs. All five mutations were traced back in the dVIN (n=5) or the LS (n=1) with frequencies ranging from 3-19%. Conclusion: Our data provide genetic evidence for a clonal relationship between VSCC and dVIN or LS.

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Supplemental Digital Content is available in the text, Genomic alterations in relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) may provide insight into the role of specific genomic events in relapse development. Along this line, comparisons between the spectrum of alterations in relapses that arise in different upfront treatment protocols may provide valuable information on the association between the tumor genome, protocol components and outcome. Here, we performed a comprehensive characterization of relapsed BCP-ALL cases that developed in the context of 3 completed Dutch upfront studies, ALL8, ALL9, and ALL10. In total, 123 pediatric BCP-ALL relapses and 77 paired samples from primary diagnosis were analyzed for alterations in 22 recurrently affected genes. We found pronounced differences in relapse alterations between the 3 studies. Specifically, CREBBP mutations were observed predominantly in relapses after treatment with ALL8 and ALL10 which, in the latter group, were all detected in medium risk-treated patients. IKZF1 alterations were enriched 2.2-fold (p = 0.01) and 2.9-fold (p

We consider the problem of designing the price of electricity by an energy provider to a pool of homogeneous loads. The energy provider is risk sensitive and considers that its energy production cost at any particular time is related to the instantaneous maximum excursion of the random aggregate demand of the loads. A statistical measure of this excursion is the α- quantile of the distribution of the individual electricity demands of the loads, or equivalently the value d α at risk α, of the electricity demand per vehicle. The price is assumed to be a known and possibly time varying function of d α . The loads are associated with individual price sensitive costs. For a very large number of loads, in particular a large fleet of electric vehicles, this results in a mean field game (MFG). The existence of an MFG equilibrium associated with a price trajectory, and the epsilon- Nash property of the resulting limiting control laws, are established in this work.

The optical properties of nanoparticle assemblies can be tailored via hybridization of plasmon modes. Isotropic core/satellite superstructures made of spherical nanoparticles are known to exhibit coupled modes with a strongly scattering (radiative) character, and provide hot spots yielding high activity in surface-enhanced Raman scattering (SERS). However, to complement this functionality with plasmonic heating, additional absorbing (non-radiative) modes are required. We introduce herein anisotropic superstructures formed by decorating a central nanorod with spherical satellite nanoparticles, which feature two coupled modes that allow application for both SERS and heating. On the basis of diffuse reflectance spectroscopy, small-angle X-ray scattering (SAXS), and electromagnetic simulations, the origin of the coupled modes is disclosed and thus serves as a basis toward alternative designs of functional superstructures. This work represents a proof-of-principle for the combination of high SERS efficiency with efficient plasmonic heating by near-infrared irradiation.

PURPOSE Fixation of anterior cruciate ligament (ACL) substitutes with non-physiological anteroposterior translation (APT) worsens outcome. The aim was to present a technique for physiological APT adjustment of the transplant in ACL reconstruction and its outcome at midterm. METHODS In a consecutive series of 28 patients (age 32 ± 11 years, 24 male), chronic ACL deficiency was treated by bone-patella-tendon-bone reconstruction. Transplant APT was adjusted to that of the contralateral uninjured ACL, measured 3, 6, and 12 months postoperatively using the Rolimeter. At a median follow-up of 5.3 years (3-8 years), 82% of the patients were re-evaluated with APT measurement and using IKDC-, Tegner-, Lysholm-Scores, conventional radiographs and MRI. RESULTS No differences in APT (mean ± SD) between uninjured and reconstructed knees were observed after adjustment (6 ± 1 versus 6 ± 1 mm, n.s.). Three months postoperatively, a statistically significant increase in APT (7 ± 1 mm) and a further increase at midterm (9 ± 2 mm) were observed. Patients scored "normal" or "nearly normal", respectively, in 79% (IKDC) and 4 (3-9) points (Tegner; median, range) or 89 ± 9 points (Lysholm; mean ± SD). Radiological evaluation showed no, minimal or moderate joint degeneration in 5, 20 and 75% of patients, respectively. MRI confirmed intact ACL transplants in all patients. CONCLUSION ACL reconstruction using the presented technique was considered successful, as patients did not suffer from subjective instability, radiographic analysis did not provide evidence for graft rupture at midterm. However, APT increase and occurrence of degenerative changes in reconstructed knees at the midterm might not be prevented even by restoration of a physiological APT in ACL reconstruction. The Rolimeter can be used for quick and easy intraoperative indirect control of the applied tension to the ACL transplant by measuring the APT to obtain physiological tensioning resulting in a satisfying outcome at midterm. LEVEL OF EVIDENCE IV.

// Junxiao Zhang 1 , Xiaoyan Wang 2 , Richarda M. de Voer 1 , Jayne Y. Hehir-Kwa 1 , Eveline J. Kamping 1 , Robbert D.A. Weren 1 , Marcel Nelen 1 , Alexander Hoischen 1 , Marjolijn J.L. Ligtenberg 1, 3 , Nicoline Hoogerbrugge 1 , Xiangling Yang 2 , Zihuan Yang 2 , Xinjuan Fan 4 , Lei Wang 2 , Huanliang Liu 2, 5 , Jianping Wang 2, * , Roland P. Kuiper 1, 6, * , Ad Geurts van Kessel 1, * 1 Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands 2 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China 3 Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands 4 Department of Pathology, the Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China 5 Department of Clinical Laboratory, the Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China 6 Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands * These authors contributed equally to this work Correspondence to: Roland P. Kuiper, email: r.kuiper@prinsesmaximacentrum.nl Jianping Wang, email: wangjpgz@126.com Keywords: molecular inversion probes, early-onset colorectal cancer, Mendelian colorectal cancer predisposition syndromes, next-generation sequencing Received: June 17, 2016 Accepted: February 12, 2017 Published: February 21, 2017 ABSTRACT The currently known Mendelian colorectal cancer (CRC) predisposition syndromes account for ~5–10% of all CRC cases, and are caused by inherited germline mutations in single CRC predisposing genes. Using molecular inversion probes (MIPs), we designed a targeted next-generation sequencing panel to identify mutations in seven CRC predisposing genes: APC, MLH1, MSH2, MSH6, PMS2, MUTYH and NTHL1 . From a consecutive series of 2,371 Chinese CRC patients, 140 familial and non-familial cases were selected that were diagnosed with CRC at or below the age of 35 years. Through MIP-based sequencing we identified pathogenic variants in six genes in 16 out of the 140 (11.4%) patients selected. In 10 patients, known pathogenic mutations in APC (five patients), MLH1 (three patients), or MSH2 (two patients) were identified. Three additional patients were found to carry novel, likely pathogenic truncating ( n = 2) and missense ( n = 1) mutations in the MSH2 gene and a concomitant loss of expression of both the MSH2 and MSH6 proteins in their respective tumor tissues. From our data, we conclude that targeted MIP-based sequencing is a reliable and cost-efficient approach to identify patients with a Mendelian CRC syndrome.

Contains fulltext : 169868.pdf (Publisher’s version ) (Open Access) Approximately 15% of pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by gene expression similar to that of BCR-ABL1-positive disease and unfavorable prognosis. This BCR-ABL1-like subtype shows a high frequency of B-cell development gene aberrations and tyrosine kinase-activating lesions. To evaluate the clinical significance of tyrosine kinase gene fusions in children with BCP-ALL, we studied the frequency of recently identified tyrosine kinase fusions, associated genetic features, and prognosis in a representative Dutch/German cohort. We identified 14 tyrosine kinase fusions among 77 BCR-ABL1-like cases (18%) and none among 76 non-BCR-ABL1-like B-other cases. Novel exon fusions were identified for RCSD1-ABL2 and TERF2-JAK2. JAK2 mutation was mutually exclusive with tyrosine kinase fusions and only occurred in cases with high CRLF2 expression. The non/late response rate and levels of minimal residual disease in the fusion-positive BCR-ABL1-like group were higher than in the non-BCR-ABL1-like B-others (p

Contains fulltext : 171348.pdf (Publisher’s version ) (Open Access) Genetic predisposition for childhood cancer is under diagnosed. Identifying these patients may lead to therapy adjustments in case of syndrome-related increased toxicity or resistant disease and syndrome-specific screening programs may lead to early detection of a further independent malignancy. Cancer surveillance might also be warranted for affected relatives and detection of a genetic mutation can allow for reproductive counseling. Here we present an easy-to-use selection tool, based on a systematic review of pediatric cancer predisposing syndromes, to identify patients who may benefit from genetic counseling. The selection tool involves five questions concerning family history, the type of malignancy, multiple primary malignancies, specific features and excessive toxicity, which results in the selection of those patients that may benefit from referral to a clinical geneticist.

A rare adverse event of a right-sided pneumectomy with an elevated hemidiaphragm is right-to-left shunting through a patent foramen ovale. In this case report we describe our experience with plication of the right hemidiaphragm with instantaneous hemodynamic results and pain relief, followed by secondary closure of the foramen ovale.

Electric thermal loads, such as those for space heaters, water heaters and air conditioners, due to their association with energy storage, are deferrable. Thus, they can become an effective tool to compensate for the mismatches between power generation and power demand induced by renewable sources. Load reduction and load increase may appear to be equivalent to generation increase and generation withdrawal, but there is a significant difference in the associated post-load-control energy rebound phenomena. These phenomena can provoke undesirable post-load-control changes in the demand dynamics. The contribution of this paper is twofold. First, we define a flexibility product that load aggregators could propose that would involve a mean energy increase or decrease offer for a price and also guarantee bounds on the post-load-control deviations from normal. Second, we provide aggregators with the mathematical tools to specify the maximum load relief or increase possible under specific constraints on post-control recovery dynamics. The analysis rests on successive solutions of a linear program and exploits recent results on load control based on mean field game theory. We consider the case of aggregate electric water heater loads.

While the storage properties and the anticipation potential of many classes of power system loads (such as thermal loads) can be exploited to mitigate renewable sources variability, the challenge to do so in an optimal and coherentmanner is significant. This is due to the sheer number and dynamic diversity of the loads that can be involved in any large-scale application. The smartDESC concept is a control architecture that was developed for this purpose. It builds on the more pervasive communication means currently available (such as Advanced Metering Infrastructures), as well as the mathematical tools of (i) aggregate load modeling, (ii) renewable energy forecasting, (iii) optimizationtheory, deterministic or stochastic, and (iv) some recent developments in control of large-scale systems based ongame theory, and so-called mean-field (MF) control theory, which allow a scalable yet optimal approach to thedecentralized control of large pools of loads. This paper presents the building blocks of the smartDESC architecture,together with an associated simulator and simulation results.

We aimed at investigating whether early lung mechanics in non-intubated infants below 32 weeks of gestational age (GA) are associated with respiratory outcome. Lung mechanics were assessed by the forced oscillation technique using a mechanical ventilator (Fabian HFOi, ACUTRONIC Medical Systems AG, Hirzel, Switzerland) that superimposed small-amplitude oscillations (10 Hz) on a continuous positive airway pressure. Measurements were performed during regular tidal breathing using a face mask on days 2, 4, and 7 of life. Respiratory system resistance (Rrs) and reactance (Xrs) were computed from flow and pressure. One hundred and seventy-seven measurements were successfully performed in 68 infants. Infants had a mean (range) GA of 29.3 (24.1–31.7) weeks and a birth weight of 1257 (670–2350)g. Xrs was associated with the duration of respiratory support (R2 = 0.39, p

An efficient participation of prosumers in power system management depends on the quality of information they can obtain. Prosumers actions can be performed by automated agents that are operating in time-changing environments. Therefore, it is essential for them to deal with data stream problems in order to make reliable decisions based on the most accurate information. This paper provides an in-depth investigation of data and concept drift issues in accordance with residential prosumer agents. Additionally, the adaptation techniques, forgetting mechanisms, and learning strategies employed to handle these issues are explored. Accordingly, an approach is proposed to adapt the prosumer agent models to overcome the gradual and sudden concept drift concurrently. The suggested method is based on triggered adaptation techniques and performance-based forgetting mechanism. The results obtained in this study demonstrate that the proposed approach is capable of constructing efficient prosumer agents models with regard to the concept drift problem.

Contains fulltext : 204641.pdf (Publisher’s version ) (Open Access) Genetic abnormalities provide vital diagnostic and prognostic information in pediatric acute lymphoblastic leukemia (ALL) and are increasingly used to assign patients to risk groups. We recently proposed a novel classifier based on the copy-number alteration (CNA) profile of the 8 most commonly deleted genes in B-cell precursor ALL. This classifier defined 3 CNA subgroups in consecutive UK trials and was able to discriminate patients with intermediate-risk cytogenetics. In this study, we sought to validate the United Kingdom ALL (UKALL)-CNA classifier and reevaluate the interaction with cytogenetic risk groups using individual patient data from 3239 cases collected from 12 groups within the International BFM Study Group. The classifier was validated and defined 3 risk groups with distinct event-free survival (EFS) rates: good (88%), intermediate (76%), and poor (68%) (P < .001). There was no evidence of heterogeneity, even within trials that used minimal residual disease to guide therapy. By integrating CNA and cytogenetic data, we replicated our original key observation that patients with intermediate-risk cytogenetics can be stratified into 2 prognostic subgroups. Group A had an EFS rate of 86% (similar to patients with good-risk cytogenetics), while group B patients had a significantly inferior rate (73%, P < .001). Finally, we revised the overall genetic classification by defining 4 risk groups with distinct EFS rates: very good (91%), good (81%), intermediate (73%), and poor (54%), P < .001. In conclusion, the UKALL-CNA classifier is a robust prognostic tool that can be deployed in different trial settings and used to refine established cytogenetic risk groups.

Gislason, Gunnar H/0000-0002-0548-402X; Malynovsky, Yaroslav V/0000-0002-9118-1104; Bhatt, Deepak L./0000-0002-1278-6245; Nikolaev, Konstantin/0000-0003-4601-6203; Sherwood, Matthew/0000-0002-4305-5883; Chumakova, Galina A/0000-0002-2810-6531; Raffel, Owen C/0000-0001-5470-7050; Leonardi, Sergio/0000-0002-4800-6132; Tse, Hung Fat/0000-0002-9578-7808; Reshetko, Olga/0000-0003-3107-7636; Pereira, Helder/0000-0001-8656-4883; Racca, Vittorio/0000-0002-4465-3789; Podoleanu, Cristian/0000-0001-9987-2519; Ersanli, Murat/0000-0003-1847-3087; Muenzel, Thomas/0000-0001-5503-4150; Sandhu, Manjinder/0000-0003-2538-2079; Taskinen, Marja-Riitta/0000-0002-6229-3588; bastos, jose/0000-0002-9526-3123; Manakshe, Gajendra/0000-0002-4983-4271; Abbate, Antonio/0000-0002-1930-785X; STEG, Philippe Gabriel/0000-0001-6896-2941; Szarek, Michael/0000-0002-0046-0264; Bittner, Vera/0000-0001-9456-850X; Goodman, Shaun/0000-0001-8068-2440, WOS: 000490154300015, PubMed: 31121022, Aims the third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin-kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (>= 1.8 mmol/L) despite intensive statin therapy. in a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77-0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77-0.99; P = 0.032) and Type 2 (0.77, 0.61-0.97; P = 0.025), but not Type 4 MI. Conclusion After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. the data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types., Sanofi; Regeneron Pharmaceuticals, Supported by Sanofi and Regeneron Pharmaceuticals.

Contains fulltext : 207610.pdf (Publisher’s version ) (Closed access) BACKGROUND: Assessment of minimal residual disease (MRD) is an integral component for response monitoring and treatment stratification in acute lymphoblastic leukemia (ALL). We aimed to evaluate the genomic ETV6-RUNX1 fusion sites as a single marker for MRD quantification. PROCEDURE: In a representative, uniformly treated cohort of pediatric relapsed ALL patients (n = 52), ETV6-RUNX1 fusion sites were compared to the current gold standard, immunoglobulin/T-cell receptor (Ig/TCR) gene rearrangements. RESULTS: Primer/probe sets designed to ETV6-RUNX1 fusions achieved significantly more frequent a sensitivity and a quantitative range of at least 10(-4) compared to the gold standard with 100% and 73% versus 76% and 47%, respectively. The breakpoint sequence was identical at diagnosis and relapse in all tested cases. There was a high degree of concordance between quantitative MRD results assessed using ETV6-RUNX1 and the highest Ig/TCR marker (Spearman's 0.899, P < .01) with differences >(1/2) log-step in only 6% of patients. A high proportion of ETV6-RUNX1-positive ALL relapses (40%) in our cohort showed a poor response to induction treatment at relapse, and therefore had an indication for hematopoietic stem cell transplantation, demonstrating the need of accurate identification of this subgroup. CONCLUSIONS: ETV6-RUNX1 fusion sites are highly sensitive and reliable MRD markers. Our data confirm that they are unaffected by clonal evolution and selection during front-line and second-line chemotherapy in contrast to Ig/TCR rearrangements, which require several markers per patient to compensate for the observed loss of target clones. In future studies, the genomic ETV6-RUNX1 fusion can be used as single MRD marker.

Patients with inborn errors of immunity or DNA repair defects are at significant risk of developing malignancy and this complication of their underlying condition represents a substantial cause of morbidity and mortality. Whilst this risk is increasingly well-recognized, our understanding of the causative mechanisms remains incomplete. Diagnosing cancer is challenging in the presence of underlying co-morbidities and frequently other inflammatory and lymphoproliferative processes. We lack a structured approach to management despite recognizing the competing challenges of poor response to therapy and increased risk of toxicity. Finally, clinicians need guidance on how to screen for malignancy in many of these predisposing immunodeficiencies. In order to begin to address these challenges, we brought together representatives of European Immunology and Pediatric Haemato-Oncology to define the current state of our knowledge and identify priorities for clinical and research development. We propose key developmental priorities which our two communities will need to work together to address, collaborating with colleagues around the world.

Background: The assessment of lung mechanics in preterm infants is of potential value for the early evaluation of lung disease and pulmonary outcomes. We aimed (i) to identify early predictors of respiratory outcome from lung mechanics obtained in week 1 of life in preterm infants below 32 weeks gestational age (GA) and (ii) to evaluate which clinical factors are associated with lung mechanics at 36 weeks postmenstrual age (PMA). Methods: Lung mechanics were assessed by the Forced Oscillation Technique using a mechanical ventilator (Fabian HFOi, Acutronic, Hirzel, Switzerland) that superimposed small amplitude oscillations (10 Hz) on a continuous positive pressure during spontaneous tidal breathing in unsedated infants. Reactance (Xrs), representing the elasticity of the respiratory system, was computed from flow and pressure data. Measurements were performed on days 2, 4, and 7 of life and at 36 PMA. Results: 61 infants (GA 29.2±1.9 w , weight 1225±376 g, respiratory support 24±21 d, supplemental O2 6 ± 15 d) were studied. There was a significant negative association between the duration of respiratory support and Xrs measured on days 2 and 7. A multilevel model including Xrs on days 2 and 7 and GA explained 54% of the variability in duration of respiratory support vs 38% explained by a model including only GA. Xrs at 36 weeks PMA was not significantly associated with either GA, birth weight, days of respiratory support or O2 requirement. Conclusion: Early assessment of Xrs has the potential to improve prediction of pulmonary outcome.