402 research outputs found

    Severe mesenteric ischemia with multiple organ failure in a patient previously treated with a humanized monoclonal antibody against programmed death receptor-1 (pembrolizumab), a case of pembrolizumab associated catastrophic antiphospholipid syndrome?

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    Immune checkpoint inhibitors are used in the treatment of different types of tumors including melanoma and non-small cell lung carcinoma. The use of these inhibitors is associated with a broad spectrum of immune-related adverse effects. Here we report a case of a patient admitted to the intensive care unit with multiple organ failure due to catastrophic antiphospholipid syndrome following treatment with pembrolizumab, an immune checkpoint inhibitor, because of metastatic melanoma. The presented patient had multiple organ failure of lung, gastro-intestinal, renal, and the liver. Vascular thrombosis was confirmed by both imaging (pulmonary embolism on computed tomography-thorax) and histopathological examination of the intestines. In combination with the presence of IgA anti-cardiolipin antibodies and initially IgM anti-cardiolipin antibodies, catastrophic antiphospholipid syndrome was suspected. Despite treatment with plasmapheresis and corticosteroids, the patient died due to multiple organ failure. Catastrophic antiphospholipid syndrome is difficult to recognize and has high mortality rates despite supportive treatment. In this case report, discussion is provided regarding the possible immunological mechanism behind catastrophic antiphospholipid syndrome during or after treatment with immune checkpoint inhibitors. It is important to realize that in modern intensive care unit, more patients with immune-related adverse effects of the treatment with immune checkpoint inhibitors will be admitted, because of an increase in the number of patients treated with these checkpoint inhibitors. When these patients are admitted on the intensive care unit, multi-disciplinary consultation is important because of the difficulty of early recognition and optimal treatment of these possible lethal side effects

    The Relationships of Leptin, Adiponectin Levels and Paraoxonase Activity with Metabolic and Cardiovascular Risk Factors in Females Treated with Psychiatric Drugs

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    OBJECTIVES: The aim of this study was to investigate serum leptin, adiponectin and paraoxonase1 levels in adult females receiving pharmacotherapy for various psychiatric disorders. METHODS: The study group consisted of 32 obese females (mean age 40.53 ± 11.00 years, mean body mass index 35.44 ± 5.33 kg/m²) who were receiving treatment for psychiatric disorders, and the control group included 22 obese females (mean age 35.95 ± 9.16 years, mean body mass index 30.78 ± 3.33 kg/m²) who were free of psychiatric disorders. Analyses were performed using a bioelectrical impedance device. Fasting blood samples were obtained for complete blood count and various biochemical tests, including determination of leptin, adiponectin and paraoxonase1 activity. RESULTS: Body mass index, waist and hip circumference, body fat percentage, fasting blood glucose, insulin, glycosylated hemoglobin, homeostasis model assesment of insulin resistance, alanine transaminase, aspartate tarnsaminase, and leptin levels were significantly higher in the study group than in controls. Although body weight was positively correlated with leptin levels in both groups, body weight was negatively correlated with adiponectin levels in the control group and positively correlated with adiponectin levels in the study group. In the study group, body mass index and hip circumference correlated positively with leptin levels, hip circumference correlated positively with adiponectin levels, and waist to hip ratio correlated positively with paraoxonase levels. In the control group, body mass index as well as waist and hip circumferences were positively correlated with leptin levels. Weight, body mass index, and hip circumference were also negatively correlated with the adiponectin/leptin ratio in the control group. CONCLUSION: This study indicates a higher risk for obesity-related disorders, particularly metabolic syndrome, diabetes and cardiovascular disease, in patients treated with psychiatric drugs

    Locoregional Residual Esophageal Cancer after Neo-adjuvant Chemoradiotherapy and Surgery Regarding Anatomic Site and Radiation Target Fields A Histopathologic Evaluation Study:A Histopathologic Evaluation Study

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    OBJECTIVE: Neoadjuvant chemoradiotherapy followed by surgery establishes a considerable pathologic complete response (pCR) in EC. The aim was to determine site of residual tumor and its prognostic impact. SUMMARY BACKGROUND DATA: High rates of residual tumor in the adventitial region even inside the radiation fields will influence current decision-making. METHODS: We evaluated resection specimens with marked target fields from 151 consecutive EC patients treated with carboplatin/paclitaxel and 41.4Gy between 2009 and 2018. RESULTS: In radically resected (R0) specimens 19.8% (27/136) had a pCR (ypT0N0) and 14% nearly no response (tumor regression grade: tumor regression grade 4-5). Residual tumor commonly extended in or restricted to the adventitia (43.1%; 47/109), whereas 7.3% was in the mucosa (ypT1a), 16.5% in the submucosa (ypT1b) and 6.4% only in lymph nodes (ypT0N+). Macroscopic residues in R0-specimens of partial responders (tumor regression grade 2-3: N = 90) were found in- and outside the gross tumor volume (GTV) in 33.3% and 8.9%, and only microscopic in- and outside the clinical target volume in 58.9% and 1.1%, respectively. Residual nodal disease was observed proximally and distally to the clinical target volume in 2 and 5 patients, respectively. Disease Free Survival decreased significantly if macroscopic tumor was outside the GTV and in ypT2-4aN+. CONCLUSIONS: After neoadjuvant chemoradiotherapy, pCR and ypT1aN0 were seen in a limited number of R0 resected specimens (19.8% and 7.3%, respectively), whereas 6.4% had only nodal disease (yT0N+). Disease Free Survival decreased significantly if macroscopic residue was outside the GTV and in responders with only nodal disease. Therefore, we should be cautious in applying wait and see strategies

    Neuroendocrine tumours and their microenvironment

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    Tumours can escape the immune system by expressing programmed death-ligand-1 (PD-L1), which allows them to bind to PD-1 on T-cells and avoid recognition by the immune system. Regulatory T-cells (Tregs), indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) also play a role in immune suppression. Knowledge about the interaction of neuroendocrine tumours (NETs) with their immune microenvironment and the role of immunotherapy in patients with NET is scarce. Here, we investigated the immune microenvironment of serotonin-producing (SP) and non-serotonin-producing NETs (NSP-NETs). Tumours of 33 patients with SP-NET and 18 patients with NSP-NET were studied. Immunohistochemical analyses were performed for PD-L1, T-cells, IDO, TDO, mismatch repair proteins (MMRp) and activated fibroblasts. PD-L1 expression was seen in <1% of tumour and T-cells. T-cells were present in 33% of NETs, varying between 1 and 10% T-cells per high power field. IDO was expressed in tumour cells in 55% of SP-NETs and 22% of NSP-NETs (p = 0.039). TDO was expressed in stromal cells in 64% of SP-NETs and 13% of NSP-NETs (p = 0.001). No tumours had loss of MMRp. TDO-expressing stromal cells also strongly expressed alpha-SMA and were identified as cancer-associated fibroblasts (CAFs). Factors that are associated with a response to checkpoint inhibitor treatment were absent or only present to a limited extent in the tumour microenvironment of NETs. The expression of IDO and TDO in a substantial part of NETs and the presence of CAFs suggest two mechanisms that could be responsible for the cold immune microenvironment, which should be explored to enhance anti-tumour immunity and clinical responses

    Whole genome sequencing of Turkish genomes reveals functional private alleles and impact of genetic interactions with Europe, Asia and Africa

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    Background: Turkey is a crossroads of major population movements throughout history and has been a hotspot of cultural interactions. Several studies have investigated the complex population history of Turkey through a limited set of genetic markers. However, to date, there have been no studies to assess the genetic variation at the whole genome level using whole genome sequencing. Here, we present whole genome sequences of 16 Turkish individuals resequenced at high coverage (32 × -48×). Results: We show that the genetic variation of the contemporary Turkish population clusters with South European populations, as expected, but also shows signatures of relatively recent contribution from ancestral East Asian populations. In addition, we document a significant enrichment of non-synonymous private alleles, consistent with recent observations in European populations. A number of variants associated with skin color and total cholesterol levels show frequency differentiation between the Turkish populations and European populations. Furthermore, we have analyzed the 17q21.31 inversion polymorphism region (MAPT locus) and found increased allele frequency of 31.25% for H1/H2 inversion polymorphism when compared to European populations that show about 25% of allele frequency. Conclusion: This study provides the first map of common genetic variation from 16 western Asian individuals and thus helps fill an important geographical gap in analyzing natural human variation and human migration. Our data will help develop population-specific experimental designs for studies investigating disease associations and demographic history in Turkey. © 2014 Alkan et al

    Increased choroidal thickness in adults with Down syndrome.

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    INTRODUCTION: People with Down syndrome (DS) are particularly susceptible to Alzheimer's disease (AD) due to the triplication of the amyloid precursor protein (APP) gene. In this cross-sectional study, we hypothesized that choroidal thinning reported in sporadic AD (sAD) is mirrored in adults with DS. METHODS: The posterior pole of the eye for 24 adults with DS and 16 age-matched controls (Ctrl) were imaged with optical coherence tomography. Choroidal thickness (ChT) was measured and analyzed in relation to cognitive status and cerebral amyloid beta (Aβ) load. RESULTS: ChT was increased in people with DS (pwDS) compared to Ctrl. This increase was associated with gender differences and positively correlated with cerebral Aβ load in a small subset. There was no significant correlation detected between ChT and age or cognitive status. DISCUSSION: In contrast to sAD this study found a significantly thicker choroid in pwDS. Whether these changes are related to Aβ pathology in DS needs further investigation

    Microstructural Evolution of Secondary Phases in the Cast Duplex Stainless Steels CD3MN and CD3MWCuN

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    The isothermal formation behavior of secondary phases in two types of duplex stainless steels (DSS), CD3MN and CD3MWCuN, was characterized. Samples were heat treated from 1 minute to 30 days at temperatures from 700°C to 900°C. Small carbide (M23C6) and nitride (Cr2N) precipitates, together with the intermetallic phases sigma and chi, were observed using scanning electron microscopy (SEM) and confirmed by transmission electron microscopy (TEM) analyses. Based on SEM analysis, time-temperature-transformation (TTT) curves for the sigma and chi phases were determined by measuring their volume fractions from backscattered electron micrographs of heat-treated and quenched sample cross sections. Resulting TTT curves showed that the maximum formation temperature for chi is lower than that for sigma, while the time to reach 1 vol pct formation is much less for sigma than it is for chi. The thermodynamic driving forces associated with the sigma and chi formation were assessed using Thermo-Calc

    Clinical selection strategy for and evaluation of intra-operative brachytherapy in patients with locally advanced and recurrent rectal cancer

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    Background and purpose: A radical resection of locally advanced rectal cancer (LARC) or recurrent rectal cancer (RRC) can be challenging. In case of increased risk of an R1 resection, intra-operative brachytherapy (IOBT) can be applied. We evaluated the clinical selection strategy for IOBT. Materials and methods: Between February 2007 and May 2018, 132 LARC/RRC patients who were scheduled for surgery with IOBT standby, were evaluated. By intra-operative inspection of the resection margin and MR imaging, it was determined whether a resection was presumed to be radical. Frozen sections were taken on indication. In case of a suspected R1 resection, IOBT (1 x 10 Gy) was applied. Histopathologic evaluation, treatment and toxicity data were collected from medical records. Results: Tumour was resected in 122 patients. IOBT was given in 42 patients of whom 54.8% (n = 23) had a histopathologically proven R1 resection. Of the 76 IOBT-omitted R0 resected patients, 17.1% (n = 13) had a histopathologically proven R1 resection. In 4 IOBT-omitted patients, a clinical R1/2 resection was seen. In total, correct clinical judgement occurred in 72.6% (n = 88) of patients. In LARC, 58.3% (n = 14) of patients were overtreated (R0, with IOBT) and 10.9% (n = 5) were undertreated (R1, without IOBT). In RRC, 26.5% (n = 9) of patients were undertreated. Conclusion: In total, correct clinical judgement occurred in 72.6% (n = 88). However, in 26.5% (n = 9) RRC patients, IOBT was unjustifiedly omitted. IOBT is accompanied by comparable and acceptable toxicity. Therefore, we recommend IOBT to all RRC patients at risk of an R1 resection as their salvage treatment. (c) 2021 The Author(s). Published by Elsevier B.V. Radiotherapy and Oncology 159 (2021) 91 & ndash;97 This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
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