Molecular Changes in Immunological Characteristics of Bone Marrow Multipotent Mesenchymal Stromal Cells in Lymphoid Neoplasia.

Immune system and bone marrow stromal cells play an important role in maintaining normal hematopoiesis. Lymphoid neoplasia disturbs not only development of immune cells, but other immune response mechanisms as well. Multipotent mesenchymal stromal cells (MSCs) of the bone marrow are involved in immune response regulation through both intercellular interactions and secretion of various cytokines. In hematological malignancies, the bone marrow stromal microenvironment, including MSCs, is altered. Aim of this study was to describe the differences of MSCs' immunological function in the patients with acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). In ALL, malignant cells arise from the early precursor cells localized in bone marrow, while in DLBCL they arise from more differentiated B-cells. In this study, only the DLBCL patients without bone marrow involvement were included. Growth parameters, surface marker expression, genes of interest expression, and secretion pattern of bone marrow MSCs from the patients with ALL and DLBCL at the onset of the disease and in remission were studied. MSCs from the healthy donors of corresponding ages were used as controls. It has been shown that concentration of MSCs in the bone marrow of the patients with ALL is reduced at the onset of the disease and is restored upon reaching remission; in the patients with DLBCL this parameter does not change. Proliferative capacity of MSCs did not change in the patients with ALL; however, the cells of the DLBCL patients both at the onset and in remission proliferated significantly faster than those from the donors. Expression of the membrane surface markers and expression of the genes important for differentiation, immunological status maintenance, and cytokine secretion differed significantly in the MSCs of the patients from those of the healthy donors and depended on nosology of the disease. Secretomes of the MSCs varied greatly; a number of proteins associated with immune response regulation, differentiation, and maintenance of hematopoietic stem cells were depleted in the secretomes of the cells from the patients. Lymphoid neoplasia leads to dramatic changes in the functional immunological status of MSCs.

DNA Copy Number Alterations and Copy Neutral Loss of Heterozygosity in Adult Ph-Negative Acute B-Lymphoblastic Leukemia: Focus on the Genes Involved.

The landscape of chromosomal aberrations in the tumor cells of the patients with B-ALL is diverse and can influence the outcome of the disease. Molecular karyotyping at the onset of the disease using chromosomal microarray (CMA) is advisable to identify additional molecular factors associated with the prognosis of the disease. Molecular karyotyping data for 36 patients with Ph-negative B-ALL who received therapy according to the ALL-2016 protocol are presented. We analyzed copy number alterations and their prognostic significance for CDKN2A/B, DMRTA, DOCK8, TP53, SMARCA2, PAX5, XPA, FOXE1, HEMGN, USP45, RUNX1, NF1, IGF2BP1, ERG, TMPRSS2, CRLF2, FGFR3, FLNB, IKZF1, RUNX2, ARID1B, CIP2A, PIK3CA, ATM, RB1, BIRC3, MYC, IKZF3, ETV6, ZNF384, PTPRJ, CCL20, PAX3, MTCH2, TCF3, IKZF2, BTG1, BTG2, RAG1, RAG2, ELK3, SH2B3, EP300, MAP2K2, EBI3, MEF2D, MEF2C, CEBPA, and TBLXR1 genes, choosing t(4;11) and t(7;14) as reference events. Of the 36 patients, only 5 (13.8%) had a normal molecular karyotype, and 31 (86.2%) were found to have various molecular karyotype abnormalities-104 deletions, 90 duplications or amplifications, 29 cases of cnLOH and 7 biallelic/homozygous deletions. We found that 11q22-23 duplication involving the BIRC3, ATM and MLL genes was the most adverse prognostic event in the study cohort.

Acute Myeloid Leukemia Causes Serious and Partially Irreversible Changes in Secretomes of Bone Marrow Multipotent Mesenchymal Stromal Cells.

In patients with acute myeloid leukemia (AML), malignant cells modify the properties of multipotent mesenchymal stromal cells (MSCs), reducing their ability to maintain normal hematopoiesis. The aim of this work was to elucidate the role of MSCs in supporting leukemia cells and the restoration of normal hematopoiesis by analyzing ex vivo MSC secretomes at the onset of AML and in remission. The study included MSCs obtained from the bone marrow of 13 AML patients and 21 healthy donors. The analysis of proteins contained in the MSCs-conditioned medium demonstrated that secretomes of patient MSCs differed little between the onset of AML and remission; pronounced differences were observed between MSC secretomes of AML patients and healthy donors. The onset of AML was accompanied by a decrease in the secretion of proteins related to ossification, transport, and immune response. In remission, but not at the onset, secretion of proteins responsible for cell adhesion, immune response, and complement was reduced compared to donors. We conclude that AML causes crucial and, to a large extent, irreversible changes in the secretome of bone marrow MSCs ex vivo. In remission, functions of MSCs remain impaired despite the absence of tumor cells and the formation of benign hematopoietic cells.

Clinical Outcomes in Patients With COVID-19 and Hematologic Disease.

BACKGROUND: Patients with hematologic diseases are at higher risk of the SARS-CoV-2 infection and more severe clinical outcomes of the coronavirus disease. CHRONOS19 is an observational prospective cohort study with the aim to determine the short and longer-term clinical outcomes, risk factors for disease severity and mortality, and rates of postinfectious immunity in patients with malignant and nonmalignant hematologic diseases and COVID-19. PATIENTS AND METHODS: Overall, 666 patients were enrolled in the study, of which 626 were included in the final data analysis. The primary endpoint was 30-days all-cause mortality. Secondary endpoints included COVID-19 complications, rates of ICU admission and mechanical ventilation, outcomes of a hematologic disease in SARS-CoV-2 infected patients, overall survival, and risk factors for disease severity and mortality. Data from 15 centers were collected at 30, 90, and 180 days after COVID-19 was diagnosed and were managed using a web-based e-data capture platform. All evaluations were performed in the pre-omicron period of COVID-19 pandemic. RESULTS: Thirty-days all-cause mortality was 18.9%. The predominant cause of death (in 80% of cases) were COVID-19 complications. At 180 days, the majority (70%) of additional deaths were due to hematologic disease progression. At a median follow-up of 5.7 [0.03-19.04] months, 6-months overall survival was 72% [95% CI: 0.69-0.76]. One-third of patients had severe SARS-CoV-2 disease. The rate of ICU admission was 22% with 77% of these patients requiring mechanical ventilation, with poor survival rate. A univariate analysis revealed that older age (≥ 60 years), male sex, malignant hematologic disease, myelotoxic agranulocytosis, transfusion dependence, refractory disease or relapse, diabetes among comorbidities, any complications, especially ARDS alone or in combination with CRS, admission to an ICU, and mechanical ventilation were associated with higher risks of mortality. Treatment of the hematologic disease was changed, postponed, or canceled in 63% of patients. At a longer follow-up (90 and 180 days), the status of the hematologic disease changed in 7.5% of patients. CONCLUSION: Patients with hematologic disease and COVID-19 have high mortality rates, predominantly due to COVID-19 complications. At a longer-term follow-up, no significant impact of COVID-19 on the course of a hematologic disease was revealed.

Outstanding negative prediction performance of solid pulmonary nodule volume AI for ultra-LDCT baseline lung cancer screening risk stratification.

OBJECTIVE: To evaluate performance of AI as a standalone reader in ultra-low-dose CT lung cancer baseline screening, and compare it to that of experienced radiologists. METHODS: 283 participants who underwent a baseline ultra-LDCT scan in Moscow Lung Cancer Screening, between February 2017-2018, and had at least one solid lung nodule, were included. Volumetric nodule measurements were performed by five experienced blinded radiologists, and independently assessed using an AI lung cancer screening prototype (AVIEW LCS, v1.0.34, Coreline Soft, Co. ltd, Seoul, Korea) to automatically detect, measure, and classify solid nodules. Discrepancies were stratified into two groups: positive-misclassification (PM); nodule classified by the reader as a NELSON-plus /EUPS-indeterminate/positive nodule, which at the reference consensus read was < 100 mm3, and negative-misclassification (NM); nodule classified as a NELSON-plus /EUPS-negative nodule, which at consensus read was ≥ 100 mm3. RESULTS: 1149 nodules with a solid-component were detected, of which 878 were classified as solid nodules. For the largest solid nodule per participant (n = 283); 61 [21.6 %; 53 PM, 8 NM] discrepancies were reported for AI as a standalone reader, compared to 43 [15.1 %; 22 PM, 21 NM], 36 [12.7 %; 25 PM, 11 NM], 29 [10.2 %; 25 PM, 4 NM], 28 [9.9 %; 6 PM, 22 NM], and 50 [17.7 %; 15 PM, 35 NM] discrepancies for readers 1, 2, 3, 4, and 5 respectively. CONCLUSION: Our results suggest that through the use of AI as an impartial reader in baseline lung cancer screening, negative-misclassification results could exceed that of four out of five experienced radiologists, and radiologists' workload could be drastically diminished by up to 86.7%.

Inter-Observer Agreement between Low-Dose and Standard-Dose CT with Soft and Sharp Convolution Kernels in COVID-19 Pneumonia.

Computed tomography (CT) has been an essential diagnostic tool during the COVID-19 pandemic. The study aimed to develop an optimal CT protocol in terms of safety and reliability. For this, we assessed the inter-observer agreement between CT and low-dose CT (LDCT) with soft and sharp kernels using a semi-quantitative severity scale in a prospective study (Moscow, Russia). Two consecutive scans with CT and LDCT were performed in a single visit. Reading was performed by ten radiologists with 3-25 years' experience. The study included 230 patients, and statistical analysis showed LDCT with a sharp kernel as the most reliable protocol (percentage agreement 74.35 ± 43.77%), but its advantage was marginal. There was no significant correlation between radiologists' experience and average percentage agreement for all four evaluated protocols. Regarding the radiation exposure, CTDIvol was 3.6 ± 0.64 times lower for LDCT. In conclusion, CT and LDCT with soft and sharp reconstructions are equally reliable for COVID-19 reporting using the "CT 0-4" scale. The LDCT protocol allows for a significant decrease in radiation exposure but may be restricted by body mass index.

Immunophenotype of Measurable Residual Blast Cells as an Additional Prognostic Factor in Adults with B-Cell Acute Lymphoblastic Leukemia.

Measurable residual disease (MRD) is a well-known independent prognostic factor in acute leukemias, and multicolor flow cytometry (MFC) is widely used to detect MRD. MFC is able not only to enumerate MRD accurately but also to describe an antigen expression profile of residual blast cells. However, the relationship between MRD immunophenotype and patient survival probability has not yet been studied. We determined the prognostic impact of MRD immunophenotype in adults with B-cell acute lymphoblastic leukemia (B-ALL). In a multicenter study RALL-2016 (NCT03462095), 267 patients were enrolled from 2016 to 2022. MRD was assessed at the end of induction (day 70) in 94 patients with B-ALL by six- or 10-color flow cytometry in the bone marrow specimens. The 4 year relapse-free survival (RFS) was lower in MRD-positive B-ALL patients [37% vs. 78% (p < 0.0001)]. The absence of CD10, positive expression of CD38, and high expression of CD58 on MRD cells worsened the 4 year RFS [19% vs. 51% (p = 0.004), 0% vs. 51% (p < 0.0001), and 21% vs. 40% (p = 0.02), respectively]. The MRD immunophenotype is associated with RFS and could be an additional prognostic factor for B-ALL patients.

Reconstructive Surgery for High-voltage Injury of Genitoperineal Area and Upper Extremities: The Uromanual Trauma Concept.

Reconstruction of tissue defects resulting from high-voltage injuries remains a serious issue in plastic surgery. For many years it has been solved by applying autologous reconstruction with rotated and revascularized flaps. We present a series outlining reconstructive practices in treatment of patients with high-voltage "uromanual" injuries. These types of injuries include a group of upper extremities and genitoperineal high-voltage trauma due to urination on an electrical source, which are rarely discussed in the literature. This study aimed to describe the algorithm of perioperative care and surgical treatment in patients with high-voltage uromanual trauma. Three male patients (mean age 26.3 years, range: 20-35 years) with traumatic injury of the genital area and the upper extremities due to high-voltage injury underwent reconstruction with a one-stage repair of defects. In one patient, the defect of the left upper extremity was eliminated by microsurgical autotransplantation of musculocutaneous thoracodorsal artery perforator flap. The genitoperineal region was repaired using rotated scrotal flaps. In two other cases, phalloplasty with a revascularized myocutaneous thoracodorsal artery perforator flap was followed by urethroplasty with a prefabricated radial forearm free flap. Hand deformities were eliminated using split-thickness skin autografts. All flaps survived. No complications were observed in the autograft harvesting areas. All cases showed good aesthetic and functional postoperative outcomes. Management of uromanual injuries should include one-stage reconstruction of upper extremities and genitoperineal defects for restoration of satisfying functional and aesthetic components crucial for patient's quality of life and socialization.

Three-Dimensional Description of the Angular Artery in the Nasolabial Fold.

BACKGROUND: Due to its arterial vasculature, the nasolabial sulcus is one of the most challenging facial regions to treat when trying to ameliorate the signs of facial aging. OBJECTIVES: The aim of the present study was to provide data on the 3-dimensional course of the angular artery within the nasolabial sulcus in relation to age, gender, and body mass index to increase safety during minimally invasive treatments. METHODS: Thee hundred nasolabial sulci from 75 males and 75 females of Russian Caucasian ethnic background (mean [standard deviation] age, 45.7 [18.7] years; mean body mass index, 25.14 [4.9] kg/m2) were analyzed. Bilateral multiplanar measurements were based on contrast-enhanced computed tomography cranial scans. RESULTS: Up to 3 arteries could be identified within the nasolabial sulcus: ~90% contained 1 arterial trunk, ~9% had 2 trunks, and ~1% had 3 trunks; females had more arteries than men. The artery is located at mean depths of 21.6 mm at the oral commissure and 8.9 mm at the nasal ala. The angular artery was lateral to the nasolabial sulcus in 100% of cases; the smallest distance between the artery and the nasolabial sulcus was at the oral commissure (11.91 [7.9] mm) and the greatest was at the nasal ala (13.73 [3.9] mm). CONCLUSIONS: In contrast to current concepts, the angular artery is not located strictly subdermal to the nasolabial sulcus but at a variable depth, and in 100% of the investigated cases lateral to the nasolabial sulcus. With increasing age, the depth and lateral distance between arteries and sulci reduces significantly, underscoring the need for special caution when injecting this site.

Frontal cephalometric landmarking: humans vs artificial neural networks.

Frontal cephalometric radiography (frontal ceph) is one of the important diagnostic methods in orthodontics and maxillofacial surgery. It allows one to determine occlusion anomalies in the transverse and vertical planes and to evaluate the symmetry of the facial skeleton relative to the median plane, including analysis of the position of the jawbone. AIM: The aim of this study was to develop an artificial neural network (ANN) for placing cephalometric points (CPs) on frontal cephs and to compare the accuracy of its performance against humans. MATERIALS AND METHODS: The study included 330 depersonalized frontal cephs: 300 cephs for training ANNs and 30 for research. Each image was imported into the ViSurgery software (Skolkovo, Russia) and the 45 CPs were arranged. The CPs were divided into three groups: 1) precise anatomical landmarks; 2) complex anatomical landmarks; and 3) indistinct anatomical landmarks. Two ANNs were used to improve the accuracy of CP placement. The first ANN solved the problem of multiclass image segmentation, and the second regression ANN was used to correct the predictions of the first ANN. The accuracy of CP placement was compared between the ANN and three groups of doctors: expert, regular, and inexperienced. Then, using the Wilcoxon t test, the hypothesis that an ANN makes fewer or as many errors as doctors in the three groups of points was tested. RESULTS: The deviation was estimated by the mean absolute error (MAE). The MAE for the points placed by the ANN, as compared with the control, was close to the average result for the regular doctor group: 2.87 mm (ANN) and 2.85 mm (regular group); 2.47 mm (expert group), and 3.61 mm (inexperienced group). The results for individual groups of points are presented. On average, the ANN places CPs no less accurately than the regular doctor group in each group of points. However, calculating all points in total, this hypothesis was rejected because the P value was 0.0056. A different result was observed among the inexperienced doctor group. Points from groups 2 and 3, as well as all points in total, were placed more accurately by the ANN (P = 0.9998, 0.2628, and 0.9982, respectively). The exception was group 1, where the points were more accurately placed by the inexperienced doctors (P = 0.0006). CONCLUSION: The results of the present study show that ANNs can achieve accuracy comparable to humans in placing CPs, and in some cases surpass the accuracy of inexperienced doctors (students, residents, graduate students).