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关键词： prognostic factor   radiotherapy   rituximab   survival   Waldeyer&apos   s ring DLBCL  

摘要： This study aimed to identify the prognostic factors in patients with Waldeyer's ring diffuse large B-cell lymphoma (WR-DLBCL), comparing the efficacy of radiotherapy (RT) for the WR-DLBCL patients in the pre-rituximab and rituximab eras. We conducted a retrospective analysis of 134 patients diagnosed with WR-DLBCL. Univariate and multivariate analyses were performed to identify the prognostic factors for WR-DLBCL. Then, we divided these patients into the rituximab plus chemotherapy group (R-chemotherapy) (n = 88) and chemotherapy group (n = 46), and the Kaplan-Meier and Cox regression model analyses were applied to investigate the treatment value of RT in both the groups. Multivariate analysis revealed international prognostic index (IPI) >= 3 and chemotherapy without rituximab as significant risk factors for the progression-free survival (PFS, IPI >= 3: p = 0.001;chemotherapy without rituximab: p = 0.002) and overall survival (OS, IPI >= 3, p < 0.001;chemotherapy without rituximab, p = 0.024). Rituximab combined with chemotherapy significantly improved PFS (p = 0.002) and OS (p = 0.006) in these patients. RT did not significantly contribute to the survival in the overall cohort analysis, whereas in the subgroup analysis, RT significantly improved the PFS (p = 0.025) and OS (p = 0.029) for the patients in the chemotherapy group, but not in the R-chemotherapy group. In conclusion, the WR-DLBCL patients could benefit from RT in the pre-rituximab era, whereas the addition of rituximab to chemotherapy significantly improved the survival of WR-DLBCL patients, and the clinical benefit of RT was reduced.

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关键词： retinal fundus images   diabetic retinopathy   hypertensive retinopathy   deep-neural network   semantic and instance-based segmentation   transfer learning   perceptual-oriented color space   DenseNet architecture   loss function  

摘要： The stage and duration of hypertension are connected to the occurrence of Hypertensive Retinopathy (HR) of eye disease. Currently, a few computerized systems have been developed to recognize HR by using only two stages. It is difficult to define specialized features to recognize five grades of HR. In addition, deep features have been used in the past, but the classification accuracy is not up-to-the-mark. In this research, a new hypertensive retinopathy (HYPER-RETINO) framework is developed to grade the HR based on five grades. The HYPER-RETINO system is implemented based on pre-trained HR-related lesions. To develop this HYPER-RETINO system, several steps are implemented such as a preprocessing, the detection of HR-related lesions by semantic and instance-based segmentation and a DenseNet architecture to classify the stages of HR. Overall, the HYPER-RETINO system determined the local regions within input retinal fundus images to recognize five grades of HR. On average, a 10-fold cross-validation test obtained sensitivity (SE) of 90.5%, specificity (SP) of 91.5%, accuracy (ACC) of 92.6%, precision (PR) of 91.7%, Matthews correlation coefficient (MCC) of 61%, F1-score of 92% and area-under-the-curve (AUC) of 0.915 on 1400 HR images. Thus, the applicability of the HYPER-RETINO method to reliably diagnose stages of HR is verified by experimental findings.

关键词： L-carnitine   Phenylacetic acid   Phenyllactic acid   Phenylpyruvic acid   Glial cells   Oxidative stress  

摘要： Although phenylalanine (Phe) is known to be neurotoxic in phenylketonuria (PKU), its exact pathogenetic mechanisms of brain damage are still poorly known. Furthermore, much less is known about the role of the Phe derivatives phenylacetic (PAA), phenyllactic (PLA) and phenylpyruvic (PPA) acids that also accumulate in this this disorder on PKU neuropathology. Previous in vitro and in vivo studies have shown that Phe elicits oxidative stress in brain of rodents and that this deleterious process also occurs in peripheral tissues of phenylketonuric patients. In the present study, we investigated whether Phe and its derivatives PAA, PLA and PPA separately or in combination could induce reactive oxygen species (ROS) formation and provoke DNA damage in C6 glial cells. We also tested the role of L-carnitine (L-car), which has been recently considered an antioxidant agent and easily cross the blood brain barrier on the alterations of C6 redox status provoked by Phe and its metabolites. We first observed that cell viability was not changed by Phe and its metabolites. Furthermore, Phe, PAA, PLA and PPA, at concentrations found in plasma of PKU patients, provoked marked DNA damage in the glial cells separately and when combined. Of note, these effects were totally prevented (Phe, PAA and PPA) or attenuated (PLA) by L-car pre-treatment. In addition, a potent ROS formation also induced by Phe and PAA, whereas only moderate increases of ROS were caused by PPA and PLA. Pre-treatment with L-car also prevented Phe- and PAA-induced ROS generation, but not that provoked by PLA and PPA. Thus, our data show that Phe and its major metabolites accumulated in PKU provoke extensive DNA damage in glial cells probably by ROS formation and that L-car may potentially represent an adjuvant therapeutic agent in PKU treatment.

关键词： EBV   Hemophagocytic lymphohistiocytosis   HLH   Epstein-Barr virus   T cells  

摘要： Purpose T cell-Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (T cell-EBV-HLH) is prevalent in East Asia and has poor prognosis. Understanding of this disease is limited, and literature regarding prevalence in North America is scarce. Herein, we summarize our experience. Methods A retrospective analysis of T cell-EBV-HLH patients admitted to Children's Healthcare of Atlanta (GA, USA) from 2010 to 2020 was conducted. Additional immune studies were completed in a subset of patients. Results We report 15 patients (10 months-19 years of age) diagnosed with T cell-EBV-HLH. Nine patients were Hispanic, and the majority did not have primary HLH (p-HLH) gene defects. Soluble interleukin-2 receptor levels in T cell-EBV-HLH were significantly higher than other forms of secondary-HLH but comparable to p-HLH, and it correlated with disease severity at presentation. Natural killer cell function was decreased in most patients despite a negative workup for p-HLH. Depending on disease severity, initial therapy included dexamethasone or dexamethasone and etoposide. Refractory patients were managed with blended regimens that included one or more of the following therapies: combination chemotherapy, alemtuzumab, emapalumab, and nivolumab. Rituximab did not appreciably decrease EBV viremia in most patients. Non-critically ill patients responded well to immunosuppressive therapy and are long-term survivors without undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Alemtuzumab resulted in inflammation flare in two of the three patients. Three patients underwent allogeneic HSCT, with disease relapse noted in one. At a median follow-up of 3 years, 10 of the 15 patients are alive. Conclusion T cell-EBV-HLH occurs in the USA among the non-Asian populations, especially in those who are Hispanic.

关键词： Primary cutaneous large B-cell lymphoma   leg type   adalimumab   TNF inhibitor  

摘要： Introduction: Drug-induced primary cutaneous B-cell lymphomas are rare. Observation: A 63 year old woman was referred for a lumbar cutaneous lesion which had been rapidly growing for 1 month. Her past medical history included multiple allergies and a rheumatoid arthritis which was treated with oral methotrexate 10 mg per week and adalimumab. Methotrexate had been taken for 8 years, while adalimumab had been initiated 6 months earlier. Physical examination revealed a solitary thick, violaceous plaque of 6 X 4 cm in diameters, without enlarged lymph nodes. No fatigue, fever or pruritus were present. The first clinical hypothesis was a cutaneous B-cell lymphoma. The histological examination of a skin biopsy specimen showed a monomorphous dermal proliferation of large centroblast-like cells with large round, sometimes irregular, nuclei. Only rare reactive small cells were present. The infiltrate spared the epidermis, with a Grenz zone. The tumor cells were positive for CD45, CD20, bcl2, bcl6, MUM1, highly proliferating (Ki67 95%), and negative for CD3, CD30, CD10 and EBV/EBER. No CD21 or CD23 positive follicular dendritic cell network was identified. Fluorescence in situ hybridization showed no BCL2, BCL6 or CMYC rearrangement, while high resolution melting identified the MYD88 L265P mutation. A B-cell rearrangement was detected in the lesion. Whole body FDG-PET/CT showed a single hypermetabolic activity corresponding to the cutaneous lombar lesion, without distant tumours. Although the Borrelia burgdorferi serology was negative, a 15 days course of doxycyline 200 mg daily was given. Once the diagnosis of primary cutaneous large B-cell lymphoma, leg type (PCLBCL-LT) was made, adamimumab (but not methotrexate) was discontinued. The tumor completely disappeared within 4 months. No other TNF inhibitors were later given. No recurrence was observed after a follow-up time of 4 years. Discussion: PCDLBCL-LT are aggressive B-cell lymphomas mainly (but not exclusively) located o

关键词： Endoscopic submucosal dissection   Esophageal   Squamous cell carcinoma   Next-generation sequencing   Gastroesophageal reflux   TP53  

摘要： Background Cigarette smoking, alcohol consumption, and Lugol-voiding lesions (LVLs) are the major causative risk factors of esophageal squamous cell carcinoma (ESCC);however, reports on ESCC cases unrelated to these risk factors are very limited. Here, we investigated the clinicopathological features and etiology of such cases. Methods We retrospectively analyzed 704 consecutive superficial ESCC tumors of 512 patients who were treated with endoscopic submucosal dissection. The enrolled patients were divided into two groups-the very low-risk (VLR)-group and risk (R)-group-based on the presence of the abovementioned risks. Clinical, endoscopic, and pathological characteristics and genetic findings were assessed in both groups. Results The VLR-group consisted of 21 (4.1%) patients, who were characteristically female. Patients in the VLR-group presented gastroesophageal reflux disease (GERD), hiatal hernia, and non-open-type atrophic gastritis, and were negative for Helicobacter pylori. We found unique endoscopic features-frequently observed in the posterior wall of the middle thoracic esophagus-with a linear shape that closely resembled the erosion-like form of GERD. Additionally, histopathological examination showed that these tumors presented atypical nuclei limited to the basal and parabasal layer, sequential to the surrounding changes that presented pathological chronic inflammation of esophagitis. Evaluation of somatic mutations in cancer-related genes using next-generation sequencing revealed that the positive carcinogenic potential (TP53 mutation) of the tumors was relatively frequent in the VLR-group. Conclusions Our study suggests that ESCC without major causative factors is related to GERD, with no remarkable oncogenic difference.

关键词： critical limb ischemia   cell therapy   risk factors   inherited thrombotic disorders  

摘要： Autologous cell therapy (ACT) is a new treatment for patients with no-option critical limb ischemia (NO-CLI). We evaluated the factors involved in the nonresponse to ACT in patients with CLI and diabetic foot. Diabetic patients (n = 72) with NO-CLI treated using ACT in our foot clinic over a period of 8 years were divided into responders (n = 57) and nonresponders (n = 15). Nonresponder was defined as an insufficient increase in transcutaneous oxygen pressure by <5 mm Hg, 3 months after ACT. Patient demographics, diabetes duration and treatment, and comorbidities as well as a cellular response to ACT, limb-related factors, and the presence of inherited thrombotic disorders were compared between the 2 groups. The main independent predictors for an impaired response to ACT were heterozygote Leiden mutation (OR 10.5;95% CI, 1.72-4) and homozygote methylenetetrahydrofolate reductase (MTHFR 677) mutation (OR 3.36;95% CI, 1.0-14.3) in stepwise logistic regression. Univariate analysis showed that lower mean protein C levels (P = .041) were present in nonresponders compared with responders. In conclusion, the significant predictors of an impaired response to ACT in diabetic patients with NO-CLI were inherited thrombotic disorders.

关键词： Tumor microenvironment   MHCII   Cancer cell-specific MHCII expression   NSCLC   Multispectral tissue imaging  

摘要： Introduction: In patients with NSCLC, the prognostic significance of the tumor microenvironment (TME) immune composition has been revealed using single-or dual-marker staining on sequential tissue sections. Although these studies reveal that relative abundance and localization of immune cells are important parameters, deeper analyses of the NSCLC TME are necessary to refine the potential application of these findings to clinical care. Currently, the complex spatial relationships between cells of the NSCLC TME and potential drivers contributing to its immunologic composition remain unknown. Methods: We used multispectral quantitative imaging on the lung adenocarcinoma TME in 153 patients with resected tumors. On a single slide per patient, we evaluated the TME with markers for CD3, CD8, CD14, CD19, major histocompatibility complex II (MHCII), cytokeratin, and 4',6-diamidino-2-phenylindole (DAPI). Image analysis, including tissue segmentation, phenotyping, and spatial localization, was performed. Results: Specimens wherein greater than or equal to 5% of lung cancer cells expressed MHCII (MHCIIhi TME) had increased levels of CD4(+) and CD8(+) T cells and CD14(+) cell infiltration. In the MHCIIhi TME, the immune infil-trate was closer to cancer cells and expressed an activated phenotype. Morphologic image analysis revealed cancer cells in the MHCIIhi TME more frequently interfaced with CD4(+) and CD8(+) T cells. Patients with an MHCIIhi TME experienced improved overall survival (p = 0.046). Conclusions: Lung cancer cell-specific expression of MHCII associates with levels of immune cell infiltration, spatial localization, and activation status within the TME. This suggests that cancer cell-specific expression of MHCII may represent a biomarker for the immune system's recognition and activation against the tumor. (C) 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.