Non-small cell lung cancer (NSCLC) accounts for approximately 80% of bronchogenic malignancies. The choice of therapy options, including surgery, radiation therapy, and chemotherapy-used alone or in ...combination-is based on the tumor stage. Consequently, the accurate determination of tumor size, potential infiltration of adjacent structures, mediastinal lymph node involvement, and the detection of distant metastases are of central importance. The purpose of this article is to summarize the accuracy of dual-modality FDG-PET/CT imaging in staging of NSCLC as compared with FDG-PET alone, and with FDG-PET as well as CT read side by side. Furthermore, an optimized PET/CT protocol for patients who have lung cancer is outlined.
Dementia is an evolving challenge in society, and no disease-modifying treatment exists. Diagnosis can be demanding and MR imaging may aid as a noninvasive method to increase prediction accuracy. We ...explored the use of 2D local binary pattern (LBP) extracted from FLAIR and T1 MR images of the brain combined with a Random Forest classifier in an attempt to discern patients with Alzheimer's disease (AD), Lewy body dementia (LBD), and normal controls (NC). Analysis was conducted in areas with white matter lesions (WML) and all of white matter (WM). Results from 10-fold nested cross validation are reported as mean accuracy, precision, and recall with standard deviation in brackets. The best result we achieved was in the two-class problem NC versus AD + LBD with total accuracy of 0.98 (0.04). In the three-class problem AD versus LBD versus NC and the two-class problem AD versus LBD, we achieved 0.87 (0.08) and 0.74 (0.16), respectively. The performance using 3DT1 images was notably better than when using FLAIR images. The results from the WM region gave similar results as in the WML region. Our study demonstrates that LBP texture analysis in brain MR images can be successfully used for computer based dementia diagnosis.
IgG4 immune response in Churg-Strauss syndrome Vaglio, Augusto; Strehl, Johanna D; Manger, Bernhard ...
Annals of the rheumatic diseases,
03/2012, Letnik:
71, Številka:
3
Journal Article
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T-helper type 2 responses are crucial in Churg-Strauss syndrome (CSS) and may enhance the production of IgG4 antibodies. The authors assessed the IgG4 immune response in CSS patients.
The authors ...included 46 consecutive patients with CSS (24 with active and 22 with quiescent disease), 26 with granulomatosis with polyangiitis (GPA, Wegener's), 25 with atopic asthma and 20 healthy controls and determined serum IgG, IgM, IgA, IgE and IgG subclass levels. Tissue infiltration by IgG4 plasma cells was assessed in nine patients with CSS, 10 with GPA, 22 with chronic sinusitis (11 with and 11 without eosinophilia).
IgG4 levels were markedly higher in active CSS patients than in controls (p<0.001 vs all control groups). Serum IgG4 correlated with the number of disease manifestations (r=0.52, p=0.01) and the Birmingham vasculitis activity score (r=0.64, p=0.001). Longitudinal analysis in 12 CSS cases showed that both the IgG4 level and IgG4/IgG ratio dropped during disease remission (p=3×10(-5) and p=6×10(-4), respectively). Tissue analysis did not show an increased IgG4 plasma cell infiltration in CSS biopsies compared with control groups.
Serum IgG4 levels are markedly elevated in active CSS and correlate with the number of organ manifestations and disease activity.
Endothelial nitric oxide (NO) is the primary mediator of flow-mediated dilation (FMD) in human adipose microvessels. Impaired NO-mediated vasodilation occurs after acute and chronic hypertension, ...possibly due to excess generation of reactive oxygen species (ROS). The direct role of pressure elevation in this impairment of human arteriolar dilation is not known. We tested the hypothesis that elevation in pressure is sufficient to impair FMD. Arterioles were isolated from human adipose tissue and cannulated, and vasodilation to graded flow gradients was measured before and after exposure to increased intraluminal pressure (IILP; 150 mmHg, 30 min). The mediator of FMD was determined using pharmacological agents to reduce NO N(G)-nitro-l-arginine methyl ester (l-NAME), 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO), or H2O2 polyethylene glycol (PEG)-catalase, and mitochondrial (mt) ROS was quantified using fluorescence microscopy. Exposure to IILP decreased overall FMD (max %dilation: 82.7 ± 4.9 vs. 62 ± 5.6; P < 0.05). This dilation was abolished by treatment with l-NAME prepressure and PEG-catalase after IILP (max %dilation: l-NAME: 23.8 ± 6.1 vs. 74.8 ± 8.6; PEG-catalase: 71.8 ± 5.9 vs. 24.6 ± 10.6). To examine if this change was mediated by mtROS, FMD responses were measured in the presence of the complex I inhibitor rotenone or the mitochondrial antioxidant mitoTempol. Before IILP, FMD was unaffected by either compound; however, both inhibited dilation after IILP. The fluorescence intensity of mitochondria peroxy yellow 1 (MitoPY1), a mitochondria-specific fluorescent probe for H2O2, increased during flow after IILP (%change from static: 12.3 ± 14.5 vs. 127.9 ± 57.7). These results demonstrate a novel compensatory dilator mechanism in humans that is triggered by IILP, inducing a change in the mediator of FMD from NO to mitochondria-derived H2O2.
Sustainable access to essential medicines is crucial at all times, especially during a pandemic when health-care systems are operating at maximum capacity and there is an increased demand for ...lifesaving supplies. Moreover, in pandemics, not only health-care systems but also global medicine supply chains are under severe stress. Shortages of medicines, which were common before 2020,1,2 have been exacerbated by the coronavirus disease 2019 (COVID-19) pandemic because of increased demand, lockdowns, border closures and hoarding.3,4 The supply of medicines could be improved by increasing the transparency of the complicated and fractured supply chain, starting upstream at the sources of active pharmaceutical ingredients. Production of the active pharmaceutical ingredients that form the basis of every medicine is highly concentrated in only a few countries. China is the world’s largest producer, with an estimated 40% share of global production.5 India, the world’s largest provider of generic medicines, procures almost 70% of its active pharmaceutical ingredients from China.6 Yet the exact number and geographical distribution of producers remain elusive because companies that market medicines do not publish details of the sources of their active ingredients. Producers of the active pharmaceutical ingredients of a specific medicine are known only to the marketing authorization holder and the regulatory authority – neither buyers nor the public have access to this information.
The cardiac effects of resuscitative endovascular balloon occlusion of the aorta (REBOA) are largely unknown. We hypothesized that increased afterload from REBOA would lead to cardiac injury, and ...that partial flow using endovascular variable aortic control (EVAC) would mitigate this injury.
Eighteen anesthetized swine underwent controlled 25% blood volume hemorrhage. Animals were randomized to either Zone 1 REBOA, Zone 1 EVAC, or no intervention (control) for 45 minutes. Animals were then resuscitated with shed blood, observed during critical care, and euthanized after a 6-hour total experimental time. Left ventricular function was measured with a pressure-volume catheter, and blood samples were drawn at routine intervals.
The average cardiac output during the intervention period was higher in the REBOA group (9.3 8.6-15.4 L/min) compared with the EVAC group (7.2 5.8-8.0 L/min, p = 0.01) and the control group (6.8 5.8-7.7 L/min, p < 0.01). At the end of the intervention, the preload recruitable stroke work was significantly higher in both the REBOA and EVAC groups compared with the control group (111.2 102.5-148.6 and 116.7 116.6-141.4 vs. 67.1 62.7-87.9, p = 0.02 and p < 0.01, respectively). The higher preload recruitable stroke work was maintained throughout the experiment in the EVAC group, but not in the REBOA group. Serum troponin concentrations after 6 hours were higher in the REBOA group compared with both the EVAC and control groups (6.26 ± 5.35 ng/mL vs 0.92 ± 0.61 ng/mL and 0.65 ± 0.38 ng/mL, p = 0.05 and p = 0.03, respectively). Cardiac intramural hemorrhage was higher in the REBOA group compared with the control group (1.67 ± 0.46 vs. 0.17 ± 0.18, p = 0.03), but not between the EVAC and control groups.
In a swine model of hemorrhagic shock, complete aortic occlusion resulted in cardiac injury, although there was no direct decrease in cardiac function. EVAC mitigated the cardiac injury and improved cardiac performance during resuscitation and critical care.
The Virgil Fossae region on Pluto exhibits three spatially coincident properties that are suggestive of recent cryovolcanic activity over an area approximately 300 by 200 km. Situated in the fossae ...troughs or channels and in the surrounding terrain are exposures of H2O ice in which there is entrained opaque red-colored matter of unknown composition. The H2O ice is also seen to carry spectral signatures at 1.65 and 2.2 μm of NH3 in some form, possibly as a hydrate, an ammoniated salt, or some other compound. Model calculations of NH3 destruction in H2O ice by galactic cosmic rays suggest that the maximum lifetime of NH3 in the uppermost meter of the exposed surface is ~109 years, while considerations of Lyman-α ultraviolet and solar wind charged particles suggest shorter timescales by a factor of 10 or 10000. Thus, 109 y is taken as an upper limit to the age of the emplacement event, and it could be substantially younger.
The red colorant in the ammoniated H2O in Virgil Fossae and surroundings may be a macromolecular organic material (tholin) thought to give color to much of Pluto's surface, but probably different in composition and age. Owing to the limited spectral range of the New Horizons imaging spectrometer and the signal precision of the data, apart from the H2O and NH3 signatures there are no direct spectroscopic clues to the chemistry of the strongly colored deposit on Pluto. We suggest that the colored material was a component of the fluid reservoir from which the material now on the surface in this region was erupted. Although other compositions are possible, if it is indeed a complex organic material it may incorporate organics inherited from the solar nebula, further processed in a warm aqueous environment inside Pluto.
A planet-scale stress pattern in Pluto's lithosphere induced by true polar wander, freezing of a putative interior ocean, and surface loading has caused fracturing in a broad arc west of Sputnik Planitia, consistent with the structure of Virgil Fossae and similar extensional features. This faulting may have facilitated the ascent of fluid in subsurface reservoirs to reach the surface as flows and as fountains of cryoclastic materials, consistent with the appearance of colored, ammoniated H2O ice deposits in and around Virgil Fossae. Models of a cryoflow emerging from sources in Virgil Fossae indicate that the lateral extent of the flow can be several km (Umurhan et al., 2019). The deposit over the full length (>200 km) of the main trough in the Virgil Fossae complex and extending through the north rim of Elliot crater and varying in elevation over a range of ~2.5 km, suggests that it debouched from multiple sources, probably along the length of the strike direction of the normal faults defining the graben. The source or sources of the ammoniated H2O are one or more subsurface reservoirs that may or may not connect to the global ocean postulated for Pluto's interior. Alternatives to cryovolcanism in producing the observed characteristics of the region around Virgil Fossae are explored in the discussion section of the paper.
•A tectonic structure (Virgil Fossae) on Pluto may be a source of a cryolava that has been erupted onto the planet's surface.•The cryolava consists of H2O and some form of ammonia, as well as a (NH3) signature, and a colored component thought to be complex organic matter.•Ammonia in its various forms is susceptible to destruction and its presence suggests emplacement on Pluto's surface sometime in the past billion years.•In addition to the debouchment of cryolava along fault lines in Virgil Fossae, fountaining from one or more associated sites appears to have distributed a mantling layer covering a few thousand square kilometers.•Large-scale fractures in Pluto's crust appear to have facilitated the emergence of a cryolava from one or more reservoirs in the subsurface.
Craniospinal irradiation (CSI) is indicated for adult patients diagnosed with leptomeningeal disease (LMD). Proton-based vertebral body sparing (VBS) CSI has been explored with pediatric patients to ...minimize hematologic toxicity; however, utilization of VBS in an adult population is limited. A recent phase II trial has shown efficacy of proton-based CSI to treat non-small cell lung and breast cancer with LMD. We hypothesize that VBS CSI using volumetric modulated arc therapy (VMAT) could also effectively reduce dose to vertebral bodies and surrounding organs at risk, minimizing toxicity for adult patients with LMD and comparing favorably to proton-based CSI.
Consecutive patients with LMD received VMAT VBS CSI, 30 Gy in 10 fractions, as a part of a prospective registry. Full VMAT arcs for the brain fields matched to 2 spine isocenters for the upper and lower spine were created using limited posterior arcs. To further decrease the vertebral body dose, an avoid entry and exit contour was created. Acute toxicity data were collected using Common Terminology Criteria for Adverse Events v5.
Ten adult patients were treated in this cohort. One patient experienced grade 2 neutropenia with the remaining 9 experiencing grade 1 hematologic toxicity. Three patients experienced grade 2 gastrointestinal toxicity with the remaining 7 experiencing grade 1 nausea. No patient experienced grade 3+ toxicities in this cohort. One patient experienced a 5-day delay in systemic therapy initiation due to neutropenia; otherwise, all patients planned for systemic therapy started without delay.
In this study, VMAT VBS CSI led to acceptable toxicity compared with patients treated with proton CSI on a phase 2 clinical trial. Given its promising early results, future prospective evaluation of the technique is warranted.
Methylazoxymethanol (MAM), the genotoxic metabolite of the cycad azoxyglucoside cycasin, induces genetic alterations in bacteria, yeast, plants, insects and mammalian cells, but adult nerve cells are ...thought to be unaffected. We show that the brains of adult C57BL6 wild-type mice treated with a single systemic dose of MAM acetate display DNA damage (O⁶-methyldeoxyguanosine lesions, O⁶-mG) that remains constant up to 7 days post-treatment. By contrast, MAM-treated mice lacking a functional gene encoding the DNA repair enzyme O⁶-mG DNA methyltransferase (MGMT) showed elevated O⁶-mG DNA damage starting at 48 hours post-treatment. The DNA damage was linked to changes in the expression of genes in cell-signaling pathways associated with cancer, human neurodegenerative disease, and neurodevelopmental disorders. These data are consistent with the established developmental neurotoxic and carcinogenic properties of MAM in rodents. They also support the hypothesis that early-life exposure to MAM-glucoside (cycasin) has an etiological association with a declining, prototypical neurodegenerative disease seen in Guam, Japan, and New Guinea populations that formerly used the neurotoxic cycad plant for food or medicine, or both. These findings suggest environmental genotoxins, specifically MAM, target common pathways involved in neurodegeneration and cancer, the outcome depending on whether the cell can divide (cancer) or not (neurodegeneration). Exposure to MAM-related environmental genotoxins may have relevance to the etiology of related tauopathies, notably, Alzheimer's disease.
Improved survival in metastatic germ-cell cancer Fankhauser, C.D.; Sander, S.; Roth, L. ...
Annals of oncology,
February 2018, 20180201, 2018-02-01, 2018-02-00, Letnik:
29, Številka:
2
Journal Article
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The prognostic score of the International Germ-Cell Cancer Collaborative Group (IGCCCG) in metastatic germ-cell cancers (mGCC) relies on treatments delivered before 1990. It is unclear, if this score ...is still relevant to contemporary cohorts of patients who receive modern-type chemotherapy and supportive care.
All patients who underwent cisplatin/etoposide-based first-line chemotherapy for mGCC at the University Hospital Zurich (USZ) between 1991 and 2016 were identified retrospectively. Clinical characteristics were extracted from medical charts and patients classified according to the IGCCCG score. International germ cell consensus classification: a prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 1997; 15: 594–603.). Progression-free survival (PFS) and overall survival (OS) probabilities at 5 years served as outcome parameters.
The study cohort consisted of 204 patients at a median age of 32 years and a median follow-up of 4.2 years. According to the IGCCCG score, PFS in the contemporary USZ cohort was 71% overall: 83% for good-risk, 69% for intermediate-risk and 30% for poor-risk patients, P < 0.001. OS for the entire cohort was 88%. In respect to OS, we observed no difference between good- and intermediate-risk patients (94% versus 91%, P = 0.62), but a statistically significant difference between those two risk groups and poor-risk patients, who had an OS of only 65%, P < 0.001.
Within the contemporary USZ cohort of mGCC patients no improvements in PFS probabilities were observed compared with the ones predicted by the IGCCCG score for any prognostic category, but marked improvements in OS probabilities for intermediate- and poor-risk patients, possibly due to better salvage treatments.
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