FCM marker importance for MRD assessment in T-cell acute lymphoblastic leukemia: An AIEOP-BFM-ALL-FLOW study group report.

T-lineage acute lymphoblastic leukemia (T-ALL) accounts for about 15% of pediatric and about 25% of adult ALL cases. Minimal/measurable residual disease (MRD) assessed by flow cytometry (FCM) is an important prognostic indicator for risk stratification. In order to assess the MRD a limited number of antibodies directed against the most discriminative antigens must be selected. We propose a pipeline for evaluating the influence of different markers for cell population classification in FCM data. We use linear support vector machine, fitted to each sample individually to avoid issues with patient and laboratory variations. The best separating hyperplane direction as well as the influence of omitting specific markers is considered. Ninety-one bone marrow samples of 43 pediatric T-ALL patients from five reference laboratories were analyzed by FCM regarding marker importance for blast cell identification using combinations of eight different markers. For all laboratories, CD48 and CD99 were among the top three markers with strongest contribution to the optimal hyperplane, measured by median separating hyperplane coefficient size for all samples per center and time point (diagnosis, Day 15, Day 33). Based on the available limited set tested (CD3, CD4, CD5, CD7, CD8, CD45, CD48, CD99), our findings prove that CD48 and CD99 are useful markers for MRD monitoring in T-ALL. The proposed pipeline can be applied for evaluation of other marker combinations in the future.

Exploring Dual-Energy CT Spectral Information for Machine Learning-Driven Lesion Diagnosis in Pre-Log Domain.

In this study, we proposed a computer-aided diagnosis (CADx) framework under dual-energy spectral CT (DECT), which operates directly on the transmission data in the pre-log domain, called CADxDE, to explore the spectral information for lesion diagnosis. The CADxDE includes material identification and machine learning (ML) based CADx. Benefits from DECT's capability of performing virtual monoenergetic imaging with the identified materials, the responses of different tissue types (e.g., muscle, water, and fat) in lesions at each energy can be explored by ML for CADx. Without losing essential factors in the DECT scan, a pre-log domain model-based iterative reconstruction is adopted to obtain decomposed material images, which are then used to generate the virtual monoenergetic images (VMIs) at selected n energies. While these VMIs have the same anatomy, their contrast distribution patterns contain rich information along with the n energies for tissue characterization. Thus, a corresponding ML-based CADx is developed to exploit the energy-enhanced tissue features for differentiating malignant from benign lesions. Specifically, an original image-driven multi-channel three-dimensional convolutional neural network (CNN) and extracted lesion feature-based ML CADx methods are developed to show the feasibility of CADxDE. Results from three pathologically proven clinical datasets showed 4.01% to 14.25% higher AUC (area under the receiver operating characteristic curve) scores than the scores of both the conventional DECT data (high and low energy spectrum separately) and the conventional CT data. The mean gain >9.13% in AUC scores indicated that the energy spectral-enhanced tissue features from CADxDE have great potential to improve lesion diagnosis performance.

Automated identification of cell populations in flow cytometry data with transformers.

Acute Lymphoblastic Leukemia (ALL) is the most frequent hematologic malignancy in children and adolescents. A strong prognostic factor in ALL is given by the Minimal Residual Disease (MRD), which is a measure for the number of leukemic cells persistent in a patient. Manual MRD assessment from Multiparameter Flow Cytometry (FCM) data after treatment is time-consuming and subjective. In this work, we present an automated method to compute the MRD value directly from FCM data. We present a novel neural network approach based on the transformer architecture that learns to directly identify blast cells in a sample. We train our method in a supervised manner and evaluate it on publicly available ALL FCM data from three different clinical centers. Our method reaches a median F1 score of ≈0.94 when evaluated on 519 B-ALL samples and shows better results than existing methods on 4 different datasets.

UMAP Based Anomaly Detection for Minimal Residual Disease Quantification within Acute Myeloid Leukemia.

Leukemia is the most frequent malignancy in children and adolescents, with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) as the most common subtypes. Minimal residual disease (MRD) measured by flow cytometry (FCM) has proven to be a strong prognostic factor in ALL as well as in AML. Machine learning techniques have been emerging in the field of automated MRD quantification with the objective of superseding subjective and time-consuming manual analysis of FCM-MRD data. In contrast to ALL, where supervised multi-class classification methods have been successfully deployed for MRD detection, AML poses new challenges: AML is rarer (with fewer available training data) than ALL and much more heterogeneous in its immunophenotypic appearance, where one-class classification (anomaly detection) methods seem more suitable. In this work, a new semi-supervised approach based on the UMAP algorithm for MRD detection utilizing only labels of blast free FCM samples is presented. The method is tested on a newly gathered set of AML FCM samples and results are compared to state-of-the-art methods. We reach a median F1-score of 0.794, while providing a transparent classification pipeline with explainable results that facilitates inter-disciplinary work between medical and technical experts. This work shows that despite several issues yet to overcome, the merits of automated MRD quantification can be fully exploited also in AML.

Transpedicular-Transdiscal Cement Augmentation Treatment of Thoracolumbar Fusion Proximal Junctional Failure.

BACKGROUND: Long instrumented fusions for adult deformity have a proximal junction kyphosis rate between 20% and 40%. When symptomatic, proximal junctional failure (PJF) often requires revision surgery and is associated with significant morbidity. Vertebral cement augmentation (VCA) has been used for prophylaxis against PJF but has not been previously described as treatment after onset of PJF has occurred. We describe a series of patients with PJF of long posterior spinal fusions that were treated at our institution using a novel VCA technique. METHODS: Three patients with PJF above thoracolumbopelvic fusions were retrospectively reviewed following treatment with transpedicular-transdiscal VCA. The medical record was reviewed for demographic data, outcomes scores, and radiographic images. RESULTS: Mean age was 69.3 years. Mean follow-up was 13.3 months. Mean preprocedure visual analog scale score was 8.67, and postprocedure visual analog scale score was 4.00. Mean preprocedure sagittal balance was 9.7 cm, and postprocedure sagittal balance was 5.8 cm. No patients required revision surgery for PJF in the follow-up period. CONCLUSIONS: Transpedicular-transdiscal VCA treatment for PJF is safe and may have the potential to prevent the need for revision surgery. LEVEL OF EVIDENCE: 4.

Automated Flow Cytometric MRD Assessment in Childhood Acute B- Lymphoblastic Leukemia Using Supervised Machine Learning.

Minimal residual disease (MRD) as measured by multiparameter flow cytometry (FCM) is an independent and strong prognostic factor in B-cell acute lymphoblastic leukemia (B-ALL). However, reliable flow cytometric detection of MRD strongly depends on operator skills and expert knowledge. Hence, an objective, automated tool for reliable FCM-MRD quantification, able to overcome the technical diversity and analytical subjectivity, would be most helpful. We developed a supervised machine learning approach using a combination of multiple Gaussian Mixture Models (GMM) as a parametric density model. The approach was used for finding the weights of a linear combination of multiple GMMs to represent new, "unseen" samples by an interpolation of stored samples. The experimental data set contained FCM-MRD data of 337 bone marrow samples collected at day 15 of induction therapy in three different laboratories from pediatric patients with B-ALL for which accurate, expert-set gates existed. We compared MRD quantification by our proposed GMM approach to operator assessments, its performance on data from different laboratories, as well as to other state-of-the-art automated read-out methods. Our proposed GMM-combination approach proved superior over support vector machines, deep neural networks, and a single GMM approach in terms of precision and average F 1 -scores. A high correlation of expert operator-based and automated MRD assessment was achieved with reliable automated MRD quantification (F 1 -scores >0.5 in more than 95% of samples) in the clinically relevant range. Although best performance was found, if test and training samples were from the same system (i.e., flow cytometer and staining panel; lowest median F 1 -score 0.92), cross-system performance remained high with a median F 1 -score above 0.85 in all settings. In conclusion, our proposed automated approach could potentially be used to assess FCM-MRD in B-ALL in an objective and standardized manner across different laboratories. © 2019 International Society for Advancement of Cytometry.

Aneuploidy in children with relapsed B-cell precursor acute lymphoblastic leukaemia: clinical importance of detecting a hypodiploid origin of relapse.

Aneuploidy is common in paediatric B-cell precursor acute lymphoblastic leukaemia (ALL). Specific subgroups, such as high hyperdiploidy (>50 chromosomes or DNA Index ≥1·16) and hypodiploidy (<45 chromosomes), predict outcome of patients after primary treatment. Whether aneuploidy has a prognostic value for relapsed disease is yet to be determined. Using DNA index and centromere screening by multiplex ligation-dependent probe amplification, we investigated aneuploidy in 413 children treated for first relapse of B-cell precursor ALL according to the ALL-REZ BFM 2002 protocol. Ten-year event-free survival of patients with high hyperdiploid relapses approached 70%, whereas it was only 40% in low hyperdiploid relapses. Three patients with apparent hyperdiploid relapse had TP53 mutations. In these cases, array-based allelotyping revealed a hypodiploid origin with absence of the hypodiploid founder clone (masked hypodiploidy). Collectively, patients with evident or masked hypodiploid relapses showed an extremely low event-free survival rate of 9%. Importantly, the current relapse risk stratification did not identify cases with masked hypodiploidy as high-risk patients, due to their favourable clinical presentation. In multivariate analysis, hypodiploidy proved to be an independent prognostic factor. This finding supports stratification of relapses with hypodiploid origin into high-risk arms in future trials or allocation of patients to alternative treatment approaches.

Assessment of the American College of Radiology Thyroid Imaging Reporting and Data System for Thyroid Nodule Malignancy Risk Stratification in a Pediatric Population.

OBJECTIVE: The purpose of this study is to assess the diagnostic performance of the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TIRADS) for malignancy risk in pediatric thyroid nodules. MATERIALS AND METHODS: Two radiologists reviewed ultrasound images of 74 tissue-proven thyroid nodules in 62 children. Points were given for individual features and then added to determine the ACR TI-RADS category, ranging from 1 (benign) to 5 (high suspicion). Kappa coefficients were generated to assess intra- and interobserver agreement. Generalized linear mixed-effects models were used to estimate the odds of malignancy with construction of a supplementary ROC curve. RESULTS: Fifty-four nodules were benign and 20 were malignant, with a median ACR TI-RADS category of 4 (interquartile range, 4-5). Nineteen of 20 (95.0%) malignant nodules were rated as TI-RADS category 4 or 5. There was substantial intraobserver agreement (κ = 0.69-0.77; p < 0.001) and moderate interobserver agreement (κ = 0.37; p = 0.002) for TIRADS category. Univariable analysis showed that, with every 1-unit increase of TI-RADS category, the likelihood of malignancy increased 2.63 times (95% CI, 1.08-6.41; p = 0.03). After adjusting for nodule size, TI-RADS category remained marginally associated with malignancy (adjusted odds ratio, 2.27; 95% CI, 0.93-5.54; p = 0.07). The AUC was 0.75 (95% CI, 0.64-0.86). An optimal cut point of TI-RADS category 5 was selected, with TI-RADS category 5 nodules 10.44 times (95% CI, 2.71-40.21; p < 0.0001) more likely than categories 1-4 nodules to be malignant. CONCLUSION: ACR TI-RADS discriminates well between malignant and benign nodules in a pediatric population, particularly at TI-RADS category 5.

Improving formaldehyde consumption drives methanol assimilation in engineered E. coli.

Due to volatile sugar prices, the food vs fuel debate, and recent increases in the supply of natural gas, methanol has emerged as a promising feedstock for the bio-based economy. However, attempts to engineer Escherichia coli to metabolize methanol have achieved limited success. Here, we provide a rigorous systematic analysis of several potential pathway bottlenecks. We show that regeneration of ribulose 5-phosphate in E. coli is insufficient to sustain methanol assimilation, and overcome this by activating the sedoheptulose bisphosphatase variant of the ribulose monophosphate pathway. By leveraging the kinetic isotope effect associated with deuterated methanol as a chemical probe, we further demonstrate that under these conditions overall pathway flux is kinetically limited by methanol dehydrogenase. Finally, we identify NADH as a potent kinetic inhibitor of this enzyme. These results provide direction for future engineering strategies to improve methanol utilization, and underscore the value of chemical biology methodologies in metabolic engineering.

Frequency and distribution of incidental findings deemed appropriate for S modifier designation on low-dose CT in a lung cancer screening program.

PURPOSE: To describe the frequency, distribution and reporting patterns of incidental findings receiving the Lung-RADS S modifier on low-dose chest computed tomography (CT) among lung cancer screening participants. METHODS: This retrospective investigation included 581 individuals who received baseline low-dose chest CT for lung cancer screening between October 2013 and June 2017 at a single center. Incidental findings resulting in assignment of Lung-RADS S modifier were recorded as were incidental abnormalities detailed within the body of the radiology report only. A subset of 60 randomly selected CTs was reviewed by a second (blinded) radiologist to evaluate inter-rater variability of Lung-RADS reporting. RESULTS: A total of 261 (45%) participants received the Lung-RADS S modifier on baseline CT with 369 incidental findings indicated as potentially clinically significant. Coronary artery calcification was most commonly reported, accounting for 182 of the 369 (49%) findings. An additional 141 incidentalomas of the same types as these 369 findings were described in reports but were not labelled with the S modifier. Therefore, as high as 69% (402 of 581) of participants could have received the S modifier if reporting was uniform. Inter-radiologist concordance of S modifier reporting in a subset of 60 participants was poor (42% agreement, kappa = 0.2). CONCLUSIONS: Incidental findings are commonly identified on chest CT for lung cancer screening, yet reporting of the S modifier within Lung-RADS is inconsistent. Specific guidelines are necessary to better define potentially clinically significant abnormalities and to improve reporting uniformity.

Lactoferrin is a natural inhibitor of plasminogen activation.

The plasminogen system is essential for dissolution of fibrin clots, and in addition, it is involved in a wide variety of other physiological processes, including proteolytic activation of growth factors, cell migration, and removal of protein aggregates. On the other hand, uncontrolled plasminogen activation contributes to many pathological processes (e.g. tumor cells' invasion in cancer progression). Moreover, some virulent bacterial species (e.g. Streptococci or Borrelia) bind human plasminogen and hijack the host's plasminogen system to penetrate tissue barriers. Thus, the conversion of plasminogen to the active serine protease plasmin must be tightly regulated. Here, we show that human lactoferrin, an iron-binding milk glycoprotein, blocks plasminogen activation on the cell surface by direct binding to human plasminogen. We mapped the mutual binding sites to the N-terminal region of lactoferrin, encompassed also in the bioactive peptide lactoferricin, and kringle 5 of plasminogen. Finally, lactoferrin blocked tumor cell invasion in vitro and also plasminogen activation driven by Borrelia Our results explain many diverse biological properties of lactoferrin and also suggest that lactoferrin may be useful as a potential tool for therapeutic interventions to prevent both invasive malignant cells and virulent bacteria from penetrating host tissues.

Atypically presenting kaposiform hemangioendothelioma of the knee: ultrasound findings.

Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor of early childhood and infancy. Kasabach-Merritt phenomenon, a common complication of KHE, is characterized by life-threatening thrombocytopenia, hemolytic anemia, and consumption coagulopathy. There may be atypical cases that do not present with Kasabach-Merritt phenomenon and do have atypical imaging findings. Knowledge of atypical imaging features may assist radiologists in identifying KHE. In this report, we present a 4-year-old case of KHE with atypical ultrasound findings.

Postoperative CT of the Midfacial Skeleton After Trauma: Review of Normal Appearances and Common Complications.

OBJECTIVE: The objective of this article is to describe the CT appearance of the midfacial skeleton after surgical repair of posttraumatic Le Fort, nasoorbitoethmoidal (NOE), and frontal sinus fractures. Several of the more commonly encountered complications will also be described. CONCLUSION: Surgery after midfacial trauma is aimed at restoring both form and function. Knowledge of the principal tenets of Le Fort, NOE, and frontal sinus fracture repair is vital for radiologists to accurately assess the adequacy of treatment on postoperative CT and provide meaningful reports for the surgeon.

Dual-energy Computed Tomography for the Evaluation of Enhancement of Pulmonary Nodules≤3 cm in Size.

PURPOSE: The aim of the study was to compare the accuracies of 4 different methods of assessing pulmonary nodule enhancement to distinguish benign from malignant solid pulmonary nodules using nondynamic contrast-enhanced dual-energy computed tomography. MATERIALS AND METHODS: Seventy-two patients (mean age, 62 y) underwent dual-energy chest computed tomography 3 minutes after intravenous contrast administration. Each of 118 pulmonary nodules (9±5.9 mm) were evaluated for enhancement by 4 methods: visual assessment, 3-dimensional automated postprocessing measurement tool, manually drawn region of interest with calculated iodine-related attenuation, and measurement of iodine concentration. The optimal cutoff for enhancement was defined as having the largest specificity among all cutoffs while maintaining 100% sensitivity. Accuracy of the methods was assessed with receiver operating characteristic curves. RESULTS: Ninety-three of 118 pulmonary nodules were benign (79%). Visual assessment of enhancement had sensitivity and specificity of 100% and 44%, respectively. For the automated 3-dimensional measurement tool, 20 HU was found to be the optimal threshold for defining enhancement, resulting in a specificity of 71% and a sensitivity of 100%, as well as an area under the curve (AUC) of 0.87 (95% confidence interval [CI], 0.82-0.92). The AUC was 0.79 (95% CI, 0.73-0.85) for the measured enhancement using a manually drawn region of interest. When a threshold of 21 HU was used for defining enhancement, maximum specificity was obtained (56%) while maintaining 100% sensitivity. The AUC for measured iodine concentration was 0.79 (95% CI, 0.77-0.85). At a cutoff iodine concentration of 0.6 mg/mL, the sensitivity was 100% with a specificity of 57%. CONCLUSIONS: Although use of automated postprocessing had the highest specificity while maintaining 100% sensitivity, there were only minor clinically relevant differences between measurement techniques given that no single technique misclassified a malignant nodule as nonenhancing.

Evaluating efficacy of current lung cancer screening guidelines.

Objective Current lung cancer screening criteria based primarily on outcomes from the National Lung Screening Trial may not adequately capture all subgroups of the population at risk. We aimed to evaluate the efficacy of lung cancer screening criteria recommended by the United States Preventive Services Task Force, Centers for Medicare and Medicaid Services, and the National Comprehensive Cancer Network in identifying known cases of lung cancer. Methods An investigation of the Stony Brook Cancer Center Lung Cancer Evaluation Center's database identified 1207 eligible, biopsy-proven lung cancer cases diagnosed between January 1996 and March 2016. Age at diagnosis, smoking history, and other known risk factors for lung cancer were used to determine the proportion of cases that would have met current United States Preventive Services Task Force, Centers for Medicare and Medicaid Services, and National Comprehensive Cancer Network eligibility requirements for lung cancer screening. Results Of the 1046 ever smokers in the study, 40% did not meet the National Lung Screening Trial age requirements, 20% did not have a ≥30 pack year smoking history, and approximately one-third quit smoking >15 years before diagnosis, thus deeming them ineligible for screening. Applying the United States Preventive Services Task Force, Centers for Medicare and Medicaid Services, and National Comprehensive Cancer Network eligibility criteria to the Stony Brook Cancer Center's Lung Cancer Evaluation Center cases, 49.2, 46.3, and 69.8%, respectively, would have met the current lung cancer screening guidelines. Conclusions The United States Preventive Services Task Force and Centers for Medicare and Medicaid Services eligibility criteria for lung cancer screening captured less than 50% of lung cancer cases in this investigation. These findings highlight the need to reevaluate the efficacy of current guidelines and may have major public health implications.

Strategy of robotic surgeons to exert public influence through Twitter.

BACKGROUND: Twitter is gaining growing popularity as a communication platform and potential tool to influence the public in medical matters. The aim here is to examine whether and how robotic surgeons use Twitter more influentially than other urologists. METHODS: Robotic surgeons and other urologists that tweeted at the European urology congress were compared by assessing Twitter Follower/Following Ratio, Retweet Rank and Percentile and their Twitter strategies. RESULTS: Robotic surgeons had a significantly higher Twitter Follower/Following Ratio (2.1, 1.4-2.4) and Retweet Rank percentile (92.1%, 90.5-93%) than other urologists (1.2, 0.8-2.1 and 88.9%, 87.3-91.7%, respectively). Robotic surgeons used original tweet content and links more often than other urologists (69.4% vs 53.8%, and 19.8% vs 12.5%, respectively). CONCLUSIONS: Robotic surgeons had a higher public influence on Twitter than other urologists and posted original tweets and links in tweets and profiles more frequently. This strategy might optimize Twitter use by healthcare professionals in the future. Copyright © 2016 John Wiley & Sons, Ltd.

Postoperative CT of the Orbital Skeleton After Trauma: Review of Normal Appearances and Common Complications.

OBJECTIVE: The purpose of this article is to describe both the expected and unexpected imaging features of posttraumatic defects of the orbital skeleton after surgical repair. CONCLUSION: The goal of surgery is to restore the preinjury orbital anatomy to improve function and prevent enophthalmos. Radiologists need to be cognizant of the more frequently encountered operative procedures used for orbital fracture repair, the desired goals of treatment, and common complications. This will permit accurate interpretation of postoperative CT and provide surgeons with clinically useful results.

Smac mimetic sensitizes renal cell carcinoma cells to interferon-α-induced apoptosis.

The prognosis of metastatic or relapsed renal cell carcinoma (RCC) is still very poor, highlighting the need for new treatment strategies. Here, we identify a cooperative antitumor activity of interferon-α (IFNα) together with the Smac mimetic BV6 that antagonizes antiapoptotic IAP proteins. BV6 and IFNα act together to reduce cell viability and to induce apoptosis in various RCC cell lines. Molecular studies revealed that BV6/IFNα co-treatment triggers apoptosis independently of autocrine/paracrine Tumor Necrosis Factor (TNF)α signaling, since the TNFα-blocking antibody Enbrel fails to rescue cell death. Importantly, knockdown of Receptor-Interacting Protein (RIP)1 significantly decreases BV6/IFNα-mediated apoptosis, whereas the RIP1 kinase inhibitor necrostatin-1 (Nec-1) provides no protection. This demonstrates that RIP1 protein is critically required for BV6/IFNα-induced apoptosis, while RIP1 kinase activity is dispensable, pointing to a scaffold function of RIP1. Consistently, BV6 and IFNα cooperate to trigger the interaction of RIP1, Fas-Associated Death Domain protein (FADD) and caspase-8 to form a cytosolic cell death complex that drives caspase activation. Addition of the broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) significantly protects RCC cells against BV6/IFNα-induced apoptosis, demonstrating that caspase activity is required for apoptosis. In conclusion, the combination approach of IFNα and BV6 represents a promising strategy for cooperative induction of apoptosis in RCC cells, which warrants further investigation.

Utilization of surgical safety checklists by urological surgeons in Germany: a nationwide prospective survey.

OBJECTIVES: We aimed to investigate the contemporary usage rate and habits of the WHO Surgical Safety Checklist (SSC) in German urological departments. METHODS: We designed a 26-item questionnaire that was sent to all urological departments in Germany. The primary aim of this study was to evaluate the usage rate of the SSC. Secondary aims were to compare perioperative characteristics of users vs. non-users of the SSC and to assess circumstances of the SSC application. RESULTS: A total of 213 of 234 (91 %) urological departments were users of the SSC, and 21 (9 %) were non-users. SSC users had more often a standard protocol, took less time and had fewer people involved for checking perioperative patient data compared to non-users. Financial budgeting for the SSC existed in 55 (24 %) departments and for patient safety in 73 (32 %) departments. CONCLUSIONS: The usage rate of the SSC in urological departments in Germany is high despite restricted financial budgeting. Users of the SSC profit by saving time and manpower for checking perioperative patient data.

Review of Commonly Used Serum Tumor Markers and Their Relevance for Image Interpretation.

Serum tumor markers are firmly entrenched as one of the primary tools in an oncologist's armamentarium. They can be implemented in a broad range of applications from diagnostic assistance, assessing prognosis, or guiding therapeutic decisions. However, tumor markers also have limitations, which significantly impact how they should be used. Radiologists should be familiar with the following most prevalent tumor markers, which will all be discussed here: prostate-specific antigen (prostate), carcinoembryonic antigen (colon), α-fetoprotein (hepatocellular and testicular), carbohydrate antigen 19.9 (pancreas), cancer antigen 125 (ovarian), human chorionic gonadotropin/lactic dehydrogenase (testicular), and chromogranin A (neuroendocrine). This knowledge should avoid needless intervention, enhance image interpretation, and ultimately provide optimal patient care.