Relationship of the Novel Scoring System for Lower Extremity Venous Thrombosis with Pulmonary Embolism.

RATIONALE AND OBJECTIVE: To develop a new scoring system, the "Lower extremity venous Doppler ultrasound scoring system" (LEVDUS), to predict the diagnosis of pulmonary embolism (PE) localization in patients with deep vein thrombosis (DVT). METHODS: This single-center retrospective study included 182 patients aged ≥ 18 years. We used scoring according to thrombosis localization and stage in Doppler US. Patients with PE were divided into three categories based on the pulmonary artery (PA) location on CT pulmonary angiography. LEVDUS values were compared according to the PE classification. The threshold value was determined for the diagnosis of PE in the receiver operating characteristics analysis. Factors affecting the diagnosis of PE were evaluated by logistic regression analysis. RESULTS: A total of 182 patients were included (female patients: 55.5% [101/182]). The median age of the patients was 68 (IQR, 56-77). The rates of DVT and PE were 35.2% (64/182) and 52.7% (96/182), respectively. Although the median LEVDUS and d-dimer values in the subsegmental PE group were higher, LEVDUS was statistically significant but d-dimer was not (p = 0.005 and p = 0.022, respectively). In addition, both LEVDUS and d-dimer median values in the other PE groups were statistically significantly higher than the non-PE group (p < 0.001). The cut-off value for the diagnosis of PE was LEVDUS≥ 2.5. LEVDUS was 1.2-fold higher for the presence of PE. CONCLUSION: LEVDUS provides useful information in predicting the presence of PE in patients and provides a common diagnostic language between radiologists and emergency or clinic physicians.

Analysis of sphenoid sinus and ethmoid sinus volume and asymmetry by sex: A 3D-CT study.

PURPOSE: To measure the volume of the sphenoid and ethmoid sinuses and to analyse the asymmetry index values by age/gender. METHODS: Three-dimensional (3D) Computed Tomography (CT) images of 150 individuals (75 females, 75 males) of both sexes between the ages of 18-75 were included in our study. Sphenoid and ethmoid sinus volumes were measured using the 3D Slicer software package on these images, and the asymmetry index was calculated. RESULTS: In our study, mean sphenoid sinus volume (female right: 4264.4 mm3, left: 3787.1 mm3; male right: 5201.1 mm3, left: 4818.2 mm3) and ethmoid sinus volume (female right: 3365.1 mm3, left: 3321.2 mm3; male right: 3440.9 mm3, left: 3459.5 mm3) were measured in males and females. Left sphenoid sinus values of males were statistically higher than females (p = 0.036). No statistically significant relationship existed between age, sinus volumes, and asymmetry index (p > 0.05). A statistically weak positive correlation existed between males' left sphenoid and ethmoid sinus volume (rho = 0.288; p = 0.012). There was no statistical relationship between asymmetry index in the whole group (p > 0.05). A statistically weak negative correlation was found between sphenoid and ethmoid sinus asymmetry index in males (rho=-0.352; p = 0.002). There was no statistical relationship between asymmetry index in females (p > 0.05). CONCLUSION: Knowing paranasal sinus morphology, morphometry, and asymmetry index value will be significant for preoperative and postoperative periods.

Retinoids and EZH2 inhibitors cooperate to orchestrate anti-oncogenic effects on bladder cancer cells.

The highly mutated nature of bladder cancers harboring mutations in chromatin regulatory genes opposing Polycomb-mediated repression highlights the importance of targeting EZH2 in bladder cancer. Furthermore, the critical role of the retinoic acid signaling pathway in the development and homeostasis of the urothelium, and the anti-oncogenic effects of retinoids are well established. Therefore, our aim is to simultaneously target EZH2 and retinoic acid signaling in bladder cancer to potentiate the therapeutic response. Here we report that this coordinated targeting strategy stimulates an anti-oncogenic profile, as reflected by inducing a synergistic reduction in cell viability that was associated with increased apoptosis and cell cycle arrest in a cooperative and orchestrated manner. This study characterized anti-oncogenic transcriptional reprogramming centered on the transcriptional regulator CHOP by stimulating the endoplasmic reticulum stress response. We further portrayed a molecular mechanism whereby EZH2 maintains H3K27me3-mediated repression of a subset of genes involved in unfolded protein responses, reflecting the molecular mechanism underlying this co-targeting strategy. These findings highlight the importance of co-targeting the EZH2 and retinoic acid pathway in bladder cancers and encourage the design of novel treatments employing retinoids coupled with EZH2 inhibitors in bladder carcinoma.

Effects of Patient-Based Imaging Artifacts On CT Diagnosis of COVID-19 and Its Severity.

PURPOSE: To investigate the effects of patient-induced artifacts on the diagnostic performance of the COVID-19 Reporting and Data System (CO-RADS) and the computed tomography chest severity score (CT-SS). METHODS: A single-center retrospective analysis of patients aged 18 years and older who were admitted to the authors' hospital with laboratory-confirmed COVID-19 and underwent chest CT between July and November 2021 was conducted. Patients' chest CT scans were examined by 3 radiologists for CT-SS and CO-RADS classifications. Patient-based artifacts, including metal artifacts, incomplete projection artifacts, motion artifacts, and insufficient inspiration, were identified by 3 readers who were unaware of each other. For statistical analysis, interreader agreement was investigated using Fleiss kappa () agreement analysis. RESULTS: The study population included 549 patients with a median age of 66 years (IQR, 55-75 years), 321 (58.5%) of whom were men. According to the overall CO-RADS classification, the highest interreader agreement was in patients without CT artifacts ( = 0.924), while the lowest interreader agreement was in patients with motion artifacts ( = 0.613). For the CO-RADS 1 and 2 patient groups, insufficient inspiration decreased the interreader agreement most ( = 0.712 and = 0.250, respectively). For the CO-RADS 3, 4, and 5 patient groups, motion artifacts reduced the interreader agreement most ( = 0.464, = 0.453, and = 0.705, respectively). For total CT-SS, the highest kappa value was in patients without artifacts ( = 0.574), while the lowest kappa value was in patients with motion artifacts ( = 0.374). DISCUSSION: The CT technologist can avoid patient-induced artifacts by placing patients carefully on the CT table, giving patients necessary instructions before CT acquisition, and selecting optimal scanning parameters. The authors are not aware of another study in the literature investigating the effects of patient-based artifacts on interreader agreement of CO-RADS classification and CT-SS for COVID-19. CONCLUSION: CT artifacts degrade image quality and might lead to interreader disagreement of CO-RADS classification and CT-SS for patients with COVID-19.

Effects of coronary artery calcified plaque and stent on severity and survival of COVID-19 patients: a decision tree model study.

AIM: We aimed to investigate the relationship between the presence of calcified plaques and stents in coronary arteries as evaluated by the chest computed tomography severity score (CT-SS) and mortality rates in patients with COVID-19. MATERIAL AND METHODS: A single-center retrospective analysis was conducted of 492 patients (≥18 yrs) who were hospitalized between March and June 2020. All included patients had RT-PCR tests positive for COVID-19. A radiologist recorded pulmonary imaging findings and the presence of coronary calcified plaque and / or stent, sternotomy wires, and cardiac valve replacement on initial non-contrast chest CT. Also, cardiothoracic ratios (CTR) were calculated on chest CTs. Data were analyzed using univariate and multivariate analyses and a chi-squared automatic interaction detection (CHAID) tree analysis, which was developed as a predictive model for survival of COVID-19 patients according to chest CT findings. RESULTS: The mean CT-SS value of the patients with coronary plaque was 11.88±7.88, and a significant relationship was found between CT-SS with coronary calcified plaque (p<0.001). No statistical difference was found between CT-SS and coronary stent (p=0.296). In multivariate analysis, older age was associated with 1.69­fold (p< 0.001), the presence of coronary calcified plaque 1.943­fold (p=0.034) and higher CT-SS 1.038­fold (p=0.042) higher risk of mortality. In the CHAID tree analysis, the highest mortality rate was seen in patients with coronary plaque and CTR>0.57. CONCLUSION: The presence of coronary artery calcified plaque and cardiomegaly were high risks for severe prognosis and mortality in COVID-19 patients and may help to predict the survival of patients.

Effects of nonsteroidal anti-inflammatory drugs on ultrasound findings of mRNA COVID-19 vaccine-related lymphadenopathy.

BACKGROUND: Previous studies reported axillary lymphadenopathy (LAP) as a side effect of the anti-COVID-19 vaccine. However, the effects of nonsteroidal anti-inflammatory drug (NSAID)s on mRNA COVID-19 vaccine-related LAP have not been investigated. PURPOSE: We aimed to investigate the effects of NSAIDs on temporal changes in sonographic findings of COVID-19 vaccine-associated LAP. METHODS: Our single-center retrospective cohort study was conducted between October 2021 and April 2022. We included patients (aged ≥ 18 years) who applied with complaints of swelling in the ipsilateral axillary region after the COVID-19 vaccine and had axillary region ultrasound (US) scans in electronic medical records within 30 days pre-vaccination. The serial US was performed on the third, 10th, and 30th days post-vaccination. RESULTS: Our study included 38 patients with a median age of 36 (IQR, 32-43) years. In 18 (47.4%) patients used NSAIDs in the early post-vaccination period. Measurements of LAPs on ultrasound scans increased at day 3 post-vaccination compared with pre-vaccination both in NSAID users and non-users. On the 10th day, a statistically insignificant decrease in LAP diameters and cortical thickness was observed in NSAID users compared to non-users. On the post-vaccination 30th day, axillary LAPs regressed similarly in both groups. CONCLUSION: In our study, post-vaccine NSAID use had no statistically significant effect on the course of axillary LAPs.

Is a high chest CT severity score a risk factor for an increased incidence of long-term neuroimaging findings after COVID-19?

OBJECTIVES: We aimed to determine the incidences of neuroimaging findings (NIF) and investigate the relationship between the course of pneumonia severity and neuroimaging findings. MATERIALS AND METHODS: Our study was a retrospective analysis of 272 (>18 years) COVID-19 patients who were admitted between "March 11, 2021, and September 26, 2022". All patients underwent both chest CT and neuroimaging. The patient's chest CTs were evaluated for pneumonia severity using a severity score system (CT-SS). The incidence of NIF was calculated. NIF were categorized into two groups; neuroimaging positive (NIP) and neuroimaging negative (NIN). Consecutive CT-SS changes in positive and negative NIF patients were analyzed. RESULTS: The median age of total patients was 71; IQR, 57-80. Of all patients, 56/272 (20.6%) were NIP. There was no significant relationship between NIP and mortality (p = 0.815) and ICU admission (p = 0.187). The incidences of NIF in our patients were as follows: Acute-subacute ischemic stroke: 47/272 (17.3%); Acute spontaneous intracranial hemorrhage: 13/272 (4.8%); Cerebral microhemorrhages: 10/272 (3.7%) and Cerebral venous sinus thrombosis: 3/25 (10.7%). Temporal change of CT-SSs, there was a statistically significant increase in the second and third CT-SSs compared to the first CT-SS in both patients with NIP and NIN. CONCLUSION: Our results showed that since neurological damage can be seen in the late period and neurological damage may develop regardless of pneumonia severity.

Whole Transcriptome Sequencing Reveals Cancer-Related, Prognostically Significant Transcripts and Tumor-Infiltrating Immunocytes in Mantle Cell Lymphoma.

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) subtype characterized by overexpression of CCND1 and SOX11 genes. It is generally associated with clinically poor outcomes despite recent improvements in therapeutic approaches. The genes associated with the development and prognosis of MCL are still largely unknown. Through whole transcriptome sequencing (WTS), we identified mRNAs, lncRNAs, and alternative transcripts differentially expressed in MCL cases compared with reactive tonsil B-cell subsets. CCND1, VCAM1, and VWF mRNAs, as well as MIR100HG and ROR1-AS1 lncRNAs, were among the top 10 most significantly overexpressed, oncogenesis-related transcripts. Survival analyses with each of the top upregulated transcripts showed that MCL cases with high expression of VWF mRNA and low expression of FTX lncRNA were associated with poor overall survival. Similarly, high expression of MSTRG.153013.3, an overexpressed alternative transcript, was associated with shortened MCL survival. Known tumor suppressor candidates (e.g., PI3KIP1, UBXN) were significantly downregulated in MCL cases. Top differentially expressed protein-coding genes were enriched in signaling pathways related to invasion and metastasis. Survival analyses based on the abundance of tumor-infiltrating immunocytes estimated with CIBERSORTx showed that high ratios of CD8+ T-cells or resting NK cells and low ratios of eosinophils are associated with poor overall survival in diagnostic MCL cases. Integrative analysis of tumor-infiltrating CD8+ T-cell abundance and overexpressed oncogene candidates showed that MCL cases with high ratio CD8+ T-cells and low expression of FTX or PCA3 can potentially predict high-risk MCL patients. WTS results were cross-validated with qRT-PCR of selected transcripts as well as linear correlation analyses. In conclusion, expression levels of oncogenesis-associated transcripts and/or the ratios of microenvironmental immunocytes in MCL tumors may be used to improve prognostication, thereby leading to better patient management and outcomes.

Plasma Concentrations and Cancer-Associated Mutations in Cell-Free Circulating DNA of Treatment-Naive Follicular Lymphoma for Improved Non-Invasive Diagnosis and Prognosis.

Follicular lymphoma (FL) is the second most frequent non-Hodgkin lymphoma accounting for 10-20% of all lymphomas in western countries. As a clinically heterogeneous cancer, FL occasionally undergoes histological transformation to more aggressive B cell lymphoma types that are associated with poor prognosis. Here we evaluated the potential of circulating cell-free DNA (cfDNA) to improve the diagnosis and prognosis of follicular lymphoma patients. Twenty well-characterized FL cases (13 symptomatic and 7 asymptomatic) were prospectively included in this study. Plasma cfDNA, formalin-fixed paraffin-embedded (FFPE) tumor tissue DNA, and patient-matched granulocyte genomic DNA samples were obtained from 20 treatment-naive FL cases. Ultra-deep targeted next-generation sequencing was performed with these DNA samples by using a custom-designed platform including exons and exon-intron boundaries of 110 FL related genes. Using a strict computational bioinformatics pipeline, we identified 91 somatic variants in 31 genes in treatment-naive FL cases. Selected variants were cross-validated by using PCR-Sanger sequencing. We observed higher concentrations of cfDNA and a higher overlap of somatic variants present both in cfDNA and tumor tissue DNA in symptomatic FL cases compared to asymptomatic ones. Variants known to be associated with FL pathogenesis such as STAT6 p.D419 or EZH2 p.Y646 were observed in patient-matched cfDNA and tumor tissue samples. Consistent with previous observations, high Ki-67 staining, elevated LDH levels, FDG PET/CT positivity were associated with poor survival. High plasma cfDNA concentrations or the presence of BCL2 mutations in cfDNA showed significant association with poor survival in treatment-naive patients. BCL2 mutation evaluations in cfDNA improved the prognostic utility of previously established variables. In addition, we observed that a FL patient who had progressive disease contained histological transformation-associated gene (i.e. B2M and BTG1) mutations only in cfDNA. Pre-treatment concentrations and genotype of plasma cfDNA may be used as a liquid biopsy to improve diagnosis, risk stratification, and prediction of histological transformation. Targeted therapies related to oncogenic mutations may be applied based on cfDNA genotyping results. However, the results of this study need to be validated in a larger cohort of FL patients as the analyses conducted in this study have an exploratory nature.

Mediastinal lymph node enlargement in COVID-19: Relationships with mortality and CT findings.

BACKGROUND: The presence of mediastinal lymph node enlargement (MLNE) in computed tomography (CT) of Coronavirus disease 2019 (COVID-19) patients can be associated with disease severity. OBJECTIVES: To investigate the relationship between MLNE with intensive care unit admission (ICU), mortality rates, and CT findings, especially in early-stage COVID-19 patients. METHODS: This single-center retrospective case-control study, included aged ≥18 years, 250 COVID-19 patients with positive RT-PCR tests. We included two patient groups, 125/250 with and without MLNE. Demographic information of the patients, laboratory findings, length of stay in hospital or ICU, mortality rates, initial CT imaging findings and CT severity scores (CT-SS) were recorded and their relationship with MLNE was investigated. RESULTS: Patients with MLNE were older (69.61 ± 11.16; p < 0.001) and had a higher CT-SS (14.67 ± 7.55; p < 0.001). There was a significant difference between the presence of MLNE with mortality (58/77, 75.3%; p < 0.001) and ICU admission (49/61, 80.3%; p < 0.001). Also, a statistical association was found between MLNE with ICU admission (p = 0.001) and (p < 0.001) mortality rates in patients with CORADS≤2 CT findings. In multivariate logistic regression analysis, MLNE was 8.8-fold (95% CI: 1.62-47.86, p =  0.01) more correlated with linear opacity and 0.25-fold with bronchial wall thickening (95% CI: 0.07-0.92, p =  0.04). CONCLUSION: Mediastinal lymph node enlargement is an important CT finding that can predict the severe prognosis of COVID-19 patients. Even in patients without lung involvement on initial CT, the presence of MLNE should be carefully examined as it is associated with disease severity.

PRDM1 decreases sensitivity of human NK cells to IL2-induced cell expansion by directly repressing CD25 (IL2RA).

IL2 receptor signaling is crucial for human NK cell activation and gain of effector functions. The molecular mechanisms involved in termination of IL2 activation are largely unknown in human NK cells. PR/SET domain 1 was previously reported to decrease cell growth and increase apoptosis in an IL2-dependent manner in malignant NK cell lines, suggesting the possibility of down-regulation of IL2 signaling pathway gene(s) through direct transcriptional repression. Using ChIP-Seq, we identified a PRDM1 binding site on the first intron of CD25 (IL2RA), which codes for the IL2 receptor subunit regulating sensitivity to IL2 signaling, in primary NK cells activated with engineered K562 cells or IL2. Ectopic expression of PRDM1 down-regulated CD25 expression at transcript and protein levels in two PRDM1 nonexpressing NK cell lines. shRNA-mediated knockdown of CD25 in two malignant NK cell lines led to progressive depletion of NK cells in low IL2 concentrations. By contrast, ectopic CD25 expression in primary human NK cells led to progressive increase in cell number in CD25-transduced cells in low IL2 concentrations. Altogether these results reveal a pivotal role of PRDM1 in inhibition of IL2-induced NK cell expansion through direct repression of CD25 in activated human NK cells. These observations provide additional support for the role of PRDM1 in attenuation of NK cell activation and growth, with implications on neoplastic transformation or NK cell function when it is deregulated.

Efficacy of chemical shift MRI for differentiating diffuse red bone marrow reconversion and hematological malignancies

Background/aim: The main purpose of our study was to determine the efficacy of chemical shift imaging (CSI) for differentiating diffuse red bone marrow reconversion (RBMR) and hematological malignancies. We also aimed to calculate the cut-off value for these entities with similar imaging features in routine magnetic resonance (MR) sequences. Materials and methods: A total of 54 patients were included: 17 patients (31.4%) with hematological malignancies (group 1), 16 patients (29.6%) with RBMR (group 2), and 21 patients (38.0%) with no clinical and hematological malignancies (control group). Patients with no pathological data or completed two-year follow-up and children were excluded from the study. An experienced radiologist on MRI evaluated the images blindly for final diagnosis. Pathologic results were determined as gold standard. Regions of interests (ROI) were placed on the vertebrae in CSI and signal intensity ratios (SIR) were calculated. The cut-off value was calculated using receiver operating characteristic (ROC) analysis. Results: SIR values were 0.97 ± 0.16, 0.69 ± 0.31 and 0.28 ± 0.35 (P < 0.001) for GI, G2, and G3, respectively. The cut-off value was 0.82 (P < 0.001). The sensitivity rate was 83.3% (AUC: 58%­96%), specificity was 87% (AUC: 58­98). Conclusion: CSI may be a valuable diagnostic tool for differentiating diffuse RBMR and hematological malignancies.

Whole transcriptome analysis reveals dysregulated oncogenic lncRNAs in natural killer/T-cell lymphoma and establishes MIR155HG as a target of PRDM1.

Natural killer/T-cell lymphoma is a rare but aggressive neoplasm with poor prognosis. Despite previous reports that showed potential tumor suppressors, such as PRDM1 or oncogenes associated with the etiology of this malignancy, the role of long non-coding RNAs in natural killer/T-cell lymphoma pathobiology has not been addressed to date. Here, we aim to identify cancer-associated dysregulated long non-coding RNAs and signaling pathways or biological processes associated with these long non-coding RNAs in natural killer/T-cell lymphoma cases and to identify the long non-coding RNAs transcriptionally regulated by PRDM1. RNA-Seq analysis revealed 166 and 66 long non-coding RNAs to be significantly overexpressed or underexpressed, respectively, in natural killer/T-cell lymphoma cases compared with resting or activated normal natural killer cells. Novel long non-coding RNAs as well as the cancer-associated ones such as SNHG5, ZFAS1, or MIR155HG were dysregulated. Interestingly, antisense transcripts of many growth-regulating genes appeared to be transcriptionally deregulated. Expression of ZFAS1, which is upregulated in natural killer/T-cell lymphoma cases, showed association with growth-regulating pathways such as stabilization of P53, regulation of apoptosis, cell cycle, or nuclear factor-kappa B signaling in normal and neoplastic natural killer cell samples. Consistent with the tumor suppressive role of PRDM1, we identified MIR155HG and TERC to be transcriptionally downregulated by PRDM1 in two PRDM1-null NK-cell lines when it is ectopically expressed. In conclusion, this is the first study that identified long non-coding RNAs whose expression is dysregulated in natural killer/T-cell lymphoma cases. These findings suggest that ZFAS1 and other dysregulated long non-coding RNAs may be involved in natural killer/T-cell lymphoma pathobiology through regulation of cancer-related genes, and loss-of-PRDM1 expression in natural killer/T-cell lymphomas may contribute to overexpression of MIR155HG; thereby promoting tumorigenesis.

The relationship of REL proto-oncogene to pathobiology and chemoresistance in follicular and transformed follicular lymphoma.

Follicular lymphoma (FL) is a common type of indolent lymphoma that occasionally transforms to more aggressive B-cell lymphomas. These transformed follicular lymphomas (tFL) are often associated with chemoresistance whose mechanisms are currently unknown. REL, a proto-oncogene located on frequently amplified 2p16.1-p15 locus, promotes tumorigenesis in many cancer types through deregulation of the NF-κB pathway; however, its role in FL pathobiology or chemoresistance has not been addressed. Here, we evaluated REL gene copy number by q-PCR on FFPE FL tumor samples, and observed REL amplification in 30.4% of FL cases that was associated with weak elevation of transcript levels. PCR-Sanger analysis did not show any somatic mutation in FL tumors. In support of a marginal oncogenic role, a REL-transduced FL cell line was positively selected under limiting serum conditions. Interestingly, reanalysis of previously reported gene expression profiles revealed significant enrichment of DNA damage-induced repair and cell cycle arrest pathways in tFL tumors with high REL expression compared to those with low REL expression consistent with the critical role of c-REL in genotoxicity-induced NF-κB signaling, which was reported to lead to drug resistance. In addition to DNA damage repair genes such as ATM and BRCA1, anti-apoptotic BCL2 was significantly elevated in REL-high FL and tFL tumors. Altogether these data suggest that other genes located in amplified 2p16.1-p15 locus may have more oncogenic role in FL etiology; however, high REL expression may be useful as a predictive biomarker of response to immunochemotherapy, and inhibition of c-REL may potentially sensitize resistant FL or tFL cells to chemotherapy.