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关键词： Mediastinal lymphoma   Chemo-immunotherapy   Mediastinal radiotherapy   Dose adjusted R-EPOCH   Survival outcomes  

摘要： Introduction Primary Mediastinal B cell lymphoma (PMBCL) is a biologically and clinically distinct subset of diffuse large B cell lymphoma. We analysed the outcomes of our cohort of PMBCL patients treated with Dose adjusted (DA)-R-EPOCH regimen. Patients and Methods This is a retrospective analysis of consecutive PMBCL patients who received chemotherapy consisting of DA-R-EPOCH with filgrastim support. Survival analysis was done using Kaplan-Meier method. All calculations were performed using SPSS version 20 for windows. Results A total of 43 consecutive suspected PMBCL patients were reviewed for this study, 6 patients were excluded as diagnosis of PMBCL could not be established. All patients except one (97.3%) received 6 cycles of R-DA-EPOCH regimen. Median age of the patients was 27 years (range 15-58). Bulky disease (> 7 cm) was present in 97% patients and 54% patients had extranodal disease. With a median follow up of 40 months, 3-year overall survival was 80.6% (95% CI: 74.0-87.2). The 3-year event free survival was 78.4% (95% CI: 71.6-85.2). There were 6 (16.2%) relapses, 1 (2.7%) primary progression and 7 (23%) deaths. Mediastinal radiotherapy was administered to 17 (45.9%) patients. All the deaths were due to disease progression. Grade III/IV toxicities were seen in 28 (75.7%) patients, febrile neutropenia being the most common one. Conclusions DA-R-EPOCH regimen is an effective and tolerable regimen in PMBCL patients even with adverse features.

关键词： Basal insulin   Glargine 300 U   mL   Glycemic control   Type 2 diabetes  

摘要： Introduction Insulin glargine 300 U/mL (Gla-300) is a novel glargine formulation which shows slower and more prolonged absorption following subcutaneous administration in comparison to insulin glargine 100 U/mL. In this prospective, observational, single-arm, multicenter, real-world study conducted in Serbia, we evaluated the effectiveness and safety of Gla-300 in patients with type 2 diabetes mellitus (T2DM) previously inadequately controlled with different basal or premix insulin therapy regimes. Methods A total of 350 patients with T2DM were enrolled by 27 physicians, from date of the first patient in (12 December 2017) to the date of last patient completed/last patient out (30 October 2018), from both medical centers and general hospitals. Patients' observation and data collection were performed at visit 1 (V1), i.e., the inclusion visit (3-6 months after Gla-300 introduction), including collection of retrospective data from the patients' medical charts at the time of Gla-300 introduction, and at visit 2 (V2) (3-6 months after V1). The primary objective was to assess the change in glycated hemoglobin (HbA1c) level from day of the Gla-300 initiation to the end of the observational period, while the secondary objectives included other effectiveness, as well as safety and other clinically relevant data. Results The mean age of the 350 patients was 63.4 +/- 8.4 years and 56.3% were female. The mean duration of diabetes was 13.4 +/- 7.4 years, while the mean duration of insulin therapy prior to Gla-300 initiation was 5.3 +/- 3.9 years. There was a significant reduction in HbA1c level at each visit compared to the previous visit (8.63 +/- 1.52% at baseline prior to Gla-300 initiation, 7.87 +/- 1.13% at V1, 7.45 +/- 1.05% at V2;p < 0.01 vs. previous visit) accompanied by significant reduction of all hypoglycemic events (p < 0.01). Conclusion Initiation of Gla-300 therapy significantly improved glycemic control and reduced the risk of hypoglycemia in patients with T2DM

关键词： Flash sensor glucose monitoring   HbA1c   insulin   type 2 diabetes  

摘要： Background: The real-world effect of intermittently scanned continuous glucose monitoring on glucose control in type 2 diabetes treated with basal insulin is uncertain. This retrospective real-world study aimed to evaluate change in glycated hemoglobin (HbA1c) amongst adults with type 2 diabetes managed with basal insulin starting flash glucose monitoring. Methods: Medical records were reviewed for adults with type 2 diabetes treated with basal insulin for > 1 year and using FreeStyle Libre(TM) Flash Glucose Monitoring for > 3 months. Prior to device use an HbA1c 8.0%-12.0% was recorded and a further HbA1c result was recorded 3-6 months (90-194 days) after starting device use. Results: Medical records (n = 91) analyzed from six Canadian diabetes centers showed HbA1c significantly decreased by 0.8% +/- 1.1 (mean +/- SD, [p < 0.0001]) from mean baseline HbA1c 8.9% +/- 0.9 to 8.1% +/- 1.0 at 3-6 months after initiating flash glucose monitoring. HbA1c improvement was not independently associated with age, BMI, insulin use duration, or sex. Conclusion: This Canadian real-world retrospective study showed significantly reduced HbA1c following initiation of flash glucose monitoring technology to further support management of type 2 diabetes treated with basal insulin.

关键词： angiotensins   ATP   cell physiology   intracellular calcium   meninges   potassium channels  

摘要： The meninges shield the nervous system from diverse, rather harmful stimuli and pathogens from the periphery. This tissue is composed of brain endothelial cells (BECs) that express diverse ion channels and chemical-transmitter receptors also expressed by neurons and glial cells to communicate with each other. However, information about the effects of ATP and angiotensin II on BECs is scarce, despite their essential roles in blood physiology. This work investigated in vitro if BECs from the meninges from rat forebrain respond to ATP, angiotensin II and high extracellular potassium, with intracellular calcium mobilizations and its second messenger-associated pathways. We found that in primary BEC cultures, both ATP and angiotensin II produced intracellular calcium responses linked to the activation of inositol trisphosphate receptors and ryanodine receptors, which led to calcium release from intracellular stores. We also used RT-PCR to explore what potassium channel subunits are expressed by primary BEC cultures and freshly isolated meningeal tissue, and which might be linked to the observed effects. We found that BECs mainly expressed the inward rectifier potassium channel subunits Kir1.1, Kir3.3, Kir 4.1 and Kir6.2. This study contributes to the understanding of the functions elicited by ATP and angiotensin II in BECs from rat meninges.

关键词： ablation   outcomes   renal cell carcinoma  

摘要： OBJECTIVE. The purpose of this article is to investigate the oncologic effectiveness and survival outcomes of percutaneous image-guided thermal ablation for clinical T1a renal cell carcinoma (RCC) in patients with other primary nonrenal malignancies. MATERIALS AND METHODS. We reviewed records of patients with histologically proven T1a RCC (< 4.0 cm) treated with thermal ablation over a period of 10 years between January 2005 and December 2014. We recorded past or current history of primary malignancy other than RCC, status of the primary malignancy, tumor histology (in remission or under therapy), and whether patient was currently alive or not, and if not, the date and reason of death. Three cohorts were studied: patients with RCC only (group A), patients with RCC and other primary malignancy in remission (group B), and patients with RCC and other primary malignancy under treatment (group C). The Kaplan-Meier product-limit estimator was used to estimate the survival rates. RESULTS. One hundred nine patients met the inclusion criteria (109 lesions, 110 ablation procedures). There were 46, 45, and 18 patients in the A, B, and C groups, respectively. The 5-year survival was 87%, 63%, and 40% for groups A, B, and C, respectively. The local recurrence-free survival for the whole sample was 95% at 3, 5, and 10 years. The disease-free survival was 96%, 93%, and 91% at 3, 5, and 10 years. Although a significant difference is noted between the three cohorts in overall survival (p=.02);for RCC, there were no significance differences in the local recurrence-free, disease-free, metastasis-free, and cancer-specific survivals. In addition, there was no difference in outcomes for patients in group B (in remission) when compared with those in group C (under treatment). CONCLUSION. Thermal ablation is an effective and safe modality of treatment of T1a RCC in patients with other primary malignancies that are in remission or under treatment.

摘要： Background Goblet cell carcinoids (GCC) are an aggressive, albeit rare, subtype of appendiceal tumors that exhibit distinct histologic features and lack clear treatment guidelines. We aimed to ascertain the impact of adjuvant chemotherapy (AC) for GCC in a national cohort of patients. Methods Patients who underwent a right hemicolectomy for stage I-III GCC of the appendix between 2006 and 2016 were selected from the National Cancer Database (NCDB). Stratification based on AC receipt was performed. Kaplan-Meier survival estimates and Cox proportional hazard regression were used to identify predictors of overall survival (OS). Results A total of 867 patients were identified, of whom 124 (14%) received AC. Patients in the AC group were significantly younger (54 vs. 57 years;p = 0.006) and were predominantly of male sex (60 vs. 48%;p = 0.012). On histopathology, patients in the AC group had a higher proportion of poorly/undifferentiated grade (27 vs. 5%;p < 0.001), T4 disease (35 vs. 11%;p < 0.001), and lymph node-positive disease (45 vs. 7%;p < 0.001) than patients who did not receive AC. After excluding patients diagnosed in 2016 due to a lack of follow-up data (n = 162), a survival advantage for the AC group was detected only after stratification for lymph node-positive disease (p = 0.007). On Cox proportional hazard regression, AC demonstrated an independent association with improved OS (hazard ratio 0.24, 95% confidence interval 0.084-0.683;p = 0.007). Conclusion The current analysis from the NCDB supports the role of AC for GCC of the appendix, chiefly for patients with lymph node metastatic disease.

关键词： COPD   basal cell   human primary tissue   whole RNA sequencing  

摘要： Airway basal cells are crucial for regeneration of the human lung airway epithelium and are believed to be important contributors to chronic obstructive pulmonary disease (COPD) and other lung disorders. To reveal how basal cells contribute to disease and to discover novel therapeutic targets, these basal cells need to be further characterized. In this study, we optimized a flow cytometry-based cell sorting protocol for primary human airway basal cells dependent on cell size and NGFR (nerve-growth factor receptor) expression. The basal cell population was found to be molecularly and functionally heterogeneous, in contrast to cultured basal cells. In addition, significant differences were found, such as KRT14 expression exclusively existing in cultured cells. Also, colony-forming capacity was significantly increased in cultured cells showing a clonal enrichment in vitro. Next, by single-cell RNA sequencing on primary basal cells from healthy donors and patients with Global Initiative for Chronic Obstructive Lung Disease stage IV COPD, the gene expression revealed a continuum ranging from healthy basal cell signatures to diseased basal cell phenotypes. We identified several upregulated genes that may indicate COPD, such as stress response-related genes GADD45B and AHSA1, together with with genes involved in the response to hypoxia, such as CITED2 and SOD1. Taken together, the presence of healthy basal cells in stage IV COPD demonstrates the potential for regeneration through the discovery of novel therapeutic targets. In addition, we show the importance of studying primary basal cells when investigating disease mechanisms as well as for developing future cell-based therapies in the human lung.

关键词： Non-small-cell lung cancer   Outcomes research  

摘要： Studies validating the prognostic accuracy of the tumor-node-metastases (TNM) classification in patients with lung cancer treated by neoadjuvant therapy are scarce. Tumor regression, particularly major pathological response (MPR), is an acknowledged prognostic factor in this setting. We aimed to validate a novel combined prognostic score. This retrospective single-center study was conducted on 117 consecutive patients with non-small cell lung cancer resected after neoadjuvant treatment at a Swiss University Cancer Center between 2000 and 2016. All cases were clinicopathologically re-evaluated. We assessed the prognostic performance of a novel prognostic score (PRSC) combining T-category, lymph node status, and MPR, in comparison with the eighth edition of the TNM classification (TNM8), the size adapted TNM8 as proposed by the International Association for the Study of Lung Cancer (IASLC) and MPR alone. The isolated ypT-category and the combined TNM8 stages accurately differentiated overall survival (OS, stage p = 0.004) and disease-free survival (DFS, stage p = 0.018). Tumor regression had a prognostic impact. Optimal cut-offs for MPR emerged as 65% for adenocarcinoma and 10% for non-adenocarcinoma and were statistically significant for survival (OS p = 0.006, DFS p < 0.001). The PRSC differentiated between three prognostic groups (OS and DFS p < 0.001), and was superior compared to the stratification using MPR alone or the TNM8 systems, visualized by lower Akaike (AIC) and Bayesian information criterion (BIC) values. In the multivariate analyses, stage III tumors (HR 4.956, p = 0.003), tumors without MPR (HR 2.432, p = 0.015), and PRSC high-risk tumors (HR 5.692, p < 0.001) had significantly increased risks of occurring death. In conclusion, we support 65% as the optimal cut-off for MPR in adenocarcinomas. TNM8 and MPR were comparable regarding their prognostic significance. The novel prognostic score performed distinctly better regarding OS and DFS.

关键词： basal insulin   GLP‐   1 analogue   glycaemic control   insulin therapy   type 2 diabetes  

摘要： Despite novel therapeutic options, many people with type 2 diabetes (T2D) do not achieve their HbA1c targets. Given the progressive nature of T2D, many individuals not controlled with oral therapy will require advancement to injectable therapy using either a glucagon-like peptide-1 receptor agonist (GLP-1 RA), recently recommended as a first option, or traditionally a basal insulin. However, premix insulins remain frequently used, either as initial injectable therapy or as intensification from basal insulin. Premix insulin injections can potentially provide significant glycaemic improvements to basal insulin but at the expense of increased hypoglycaemia and weight gain and the need for multiple daily doses, which may affect treatment adherence. Real-world evidence suggests that glycaemic control often remains suboptimal with premix insulins. Fixed-ratio combinations (FRCs) of basal insulin and GLP-1 RAs provide a novel alternative to premix insulin for therapy intensification. While no direct comparisons between premix insulins and FRCs are available, results from meta-analyses suggest that FRCs may offer better HbA1c reductions, a lower risk of hypoglycaemia and less weight gain compared with premix insulin in a simplified treatment regimen. A head-to-head trial of T2D treatment intensification with premix insulin and a FRC of basal insulin plus a GLP-1 RA is currently in progress, which should help to clarify the outcomes for each treatment option. This review discusses the unmet needs of people with T2D treated with premix insulin and provides evidence supporting FRCs of basal insulin and GLP-1 RAs as an alternative treatment option.