Objective To evaluate the incidence of desire for hastened death (DHD) among patients with advanced cancer and to identify factors associated with DHD. Methods This was a cross-sectional study of 227 patients with advanced cancer in Hunan Cancer Hospital. The patients were assessed using Chinese version of the Schedule of Attitudes toward Hastened Death, Karnofsky Performance Scale, Quality of Life (QOL), MD Anderson Symptom Inventory and Patient Health Questionnaire Depression Module-9. Results The number of patients with or without DHD were 71 (31.3%) and 156 (68.7%), respectively. Follow-up visits and average and high QOL were protective factors for DHD; severely disturbed sleep, symptoms that severely interfered with mood, and symptoms that severely interfered with relations with other people were risk factors for DHD. Conclusions The incidence of the DHD in patients with advanced cancer at home is high. Those who have low QOL, severely disturbed sleep, symptoms that severely interfered with mood, or symptoms that severely interfered with relations with other people should be paid attention to. These data provide a theoretical basis for the early detection and diagnosis of the desire to accelerate death of patients with advanced cancer.
Abstract Background: Regulatory T cells (Treg)/T helper (Th) 17 skewing plays a crucial role in development of acute respiratory distress (ARDS). Mesenchymal stem cells (MSCs)-secreted transforming growth factor (TGF)-β1 has remarkable immunomodulatory effects on CD4 + T cells, being environment sensitive and remains lack of discussion in hypoxic and inflammatory condition of ARDS. Methods: Purified mice splenic CD4 + T cells were pre-coated with anti-CD3 (5ug/ml) and anti-CD28 (2ug/ml) overnight. RAW264.7 cells were added as antigen presenting cells (APCs). T cells with and without RAW264.7 cells were treated with various LPS concentrations of 0,10,100,1000ng/ml or/and at hypoxia condition of 5% O2. Based on LPS (100ng/ml) and hypoxia condition (5% O2) as stimuli, MSCs were set in direct coculture or indirect coculture methods by transwell system. Anti-TGF-β1 neutralization antibody was added to explore the role of TGF-β1 among the soluble factors secreted by MSCs; miR-155 overexpression of CD4+T cells were performed by transfection and then were added to the MSCs-CD4 + T cells coculture system in hypoxic and LPS-stimulated condition. After 48 hours, cells or supernatant were collected for detection of frequency of Treg and Th17 subsets, CD4 + T cells apoptosis and proliferation capacity assay by flowcytometry, secretions of INF-γ, IL-17A, IL-21, TGF-β1 and IL-10 by ELISA, levels of miR-155, Rorc, Foxp3 and Ptpn2 mRNA expression of CD4 + T cells by RT-PCR. Results: MSCs could restore the skewed Treg/Th17 induced by LPS and hypoxia as compared to groups without MSCs with increased secretion of TGF-β1, IL-10 and IL-17A(P<0.05) and attenuate the increased expression of miR-155 in CD4 + T cells, which was independent on cell-to-cell contact mechanism while TGF-β1 neutralization could significantly inhibit the effects of MSCs restoring the skewed Treg/Th17 and abolished its effect on miR-155 expression in CD4 + T cells. Conclusions: These findings suggested miR-155 suppression of CD4 + T cells mediated MSCs-secreted TGF-β1 modulating the skewed Treg/Th17 induced by LPS-hypoxia challenge, providing evidence when proposing future T lymphocyte-targeted cell therapy in ARDS.
Regulatory T cell (Treg)/T helper (Th) 17 skewing is important in the development of acute respiratory distress syndrome (ARDS). Immunomodulatory effects of mesenchymal stem cell- (MSC-) secreted transforming growth factor- (TGF-) β1 on CD4+ T cells are environment-sensitive and lack discussion in hypoxic and inflammatory conditions.Mouse splenic CD4+ T cells were precoated with anti-CD3 (5 μg/ml) and anti-CD28 (2 μg/ml) overnight. RAW264.7 cells were added as antigen-presenting cells (APCs). T cells with and without RAW264.7 cells were treated with various LPS concentrations of 0, 10, 100, and 1000 ng/ml or/and at hypoxia condition of 5% O2. Based on LPS (100 ng/ml) and hypoxia conditions (5% O2) as stimuli, MSCs were set as direct coculture or indirect coculture by transwell system. Anti-TGF-β1 neutralization antibody was added to explore the role of TGF-β1 among the soluble factors secreted by MSCs; miR-155 overexpression of CD4+ T cells was performed by transfection, and then, cells were added to the MSC-CD4+ T cell coculture system in hypoxic- and LPS-stimulated condition. After 48 hours, cells or supernatants were collected for detection of frequency of Treg and Th17 subsets, CD4+ T cell apoptosis and proliferation capacity assay by flow cytometry, secretion of INF-γ, IL-17A, IL-21, TGF-β1, and IL-10 by ELISA, and levels of miR-155, Rorc, Foxp3, and Ptpn2 mRNA expression of CD4+ T cells by RT-PCR.MSCs could restore skewed Treg/Th17 induced by LPS and hypoxia compared to groups without MSCs with increased secretion of TGF-β1, IL-10, and IL-17A (P < 0.05) and attenuate the increased expression of miR-155 in CD4+ T cells via cell-to-cell contact mechanism while TGF-β1 neutralization significantly inhibited the effects of MSCs restoring skewed Treg/Th17 and abolished its effect on miR-155 expression in CD4+ T cells.These findings suggested miR-155 suppression of CD4+ T cells mediated MSC-secreted TGF-β1 modulating skewed Treg/Th17 induced by LPS-hypoxia challenge, providing evidence when proposing future T lymphocyte-targeted cell therapy in a specific condition.
Abstract Janus kinase-2 (JAK2)/STAT pathway activation is commonly observed in myeloproliferative neoplasms and plays an important role in disease development and progression. The V617F activating mutation in the JAK2 pseudokinase domain is found in 95% of patients with polycythemia vera (PV) and in 50-70% of patients with primary myelofibrosis (MF) or essential thrombocythemia (ET). Studies have shown the clinical efficacy of JAK2 inhibitors in treating MF in terms of a reduction in splenomegaly and relief of constitutional symptoms. A reduction in the JAK2V617F allele burden after treatment with a JAK2-targeted agent could be a surrogate for a disease-modifying effect of this therapy. To demonstrate this, a robust method that can accurately measure the JAK2V617F allele burden is required. Here, we report the development of a sensitive quantitative PCR (qPCR) assay to determine the JAK2V617F allele burden in patients treated with SAR302503, the validation of the assay in a Phase 0 clinical study and implementation in a phase II study using samples from patients with MF. The assay demonstrated robust performance, with high sensitivity (LLOD=0.05% and LLOQ=0.5%) and accuracy. A phase 0 study in MF, PV, and ET patients showed that (1) there was minimal intra-subject sampling variability in JAK2V617F allele burden, and (2) whole-blood samples are stable for at least 48 hours at ambient conditions for DNA preparation without a significant impact on JAK2V617F allele burden measurement.Of the 31 patients with intermediate-2 or high-risk MF enrolled in a phase II clinical study (NCT01420770), baseline samples were available for 29 patients and of these, 26 were JAK2V617F-positive using this assay. Of the 19/26 patients for whom samples were available at all 3 time points, the median allele burden was 93% at baseline, 87% at the end of Cycle 3, and 78% at the end of Cycle 6. Among the 24 patients who were JAK2V617F-positive and for whom spleen measurements were available at the end of Cycle 6, a total of 15 (63%) had a spleen response (≥ 35% reduction in spleen volume by MRI versus baseline). In contrast, two JAK2V617F-negative patients did not have a spleen response. Patients with baseline allele burden levels of 0 to <25%, 25% to 75%, and ≥75% showed spleen response rates of 50%, 44%, and 69%, respectively, at the end of Cycle 6. JAK2V617F allele burden will continue to be assessed every 3 cycles. Longer follow up is needed to determine the clinical effect of allele burden reduction. Citation Format: Feng Liu, Moshe Talpaz, Animesh Pardanani, Catriona Jamieson, Nashat Gabrail, Ayalew Tefferi, Tianlei Lei, Rita Greco, Francisco Adrian, Nikki Daskalakis, Claudia Lebedinsky, Pamela Cohen, Donald Bergstrom. Determination of JAK2V617F allele burden in a phase II study of patients with myelofibrosis treated with SAR302503 using a sensitive and robust allele-specific qPCR assay. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-294. doi:10.1158/1538-7445.AM2013-LB-294
Abstract Background: SAR302503 is a JAK2 inhibitor in clinical development as a treatment for myelofibrosis (MF). In a phase 1/2 study, SAR302503 provided durable reductions in spleen size and disease-related symptoms, with an acceptable safety profile in patients with MF (J Clin Oncol 2011;29:789). Methods: Healthy males between 18 and 45 years of age received seven ascending single oral doses of SAR302503 (range, 10 to 680 mg) or placebo under fasted conditions. Blood was collected before the first dose and at intervals after dosing up to 72 hrs. For the 300, 500, and 680 mg doses, samples were also collected postdose at 104 hrs and 168 hrs. Dose proportionality was assessed using an empirical power model for log-transformed Cmax, AUClast, and AUC. Dose effect was analyzed using a linear fixed effect model for log-transformed t1/2z. STAT3 phosphorylation (pSTAT3) was measured at predose, and 3 and 24 hrs postdose. The relationship between pSTAT3 suppression and SAR302503 plasma concentration was explored using an inhibitory Emax model. Results: Fifty-six subjects were treated and included in the safety assessment and 37 in the PK evaluation. Treatment-emergent adverse events (MedDRA v14.1) were all mild in intensity and reported by 20 of 42 subjects (48%) who received SAR302503 and by 3/14 (21%) who received placebo. There were no deaths or serious adverse events. The most frequently reported adverse events with SAR302503 were gastrointestinal occurring in 1 of 6 subjects at both the 80 and 150 mg doses, 3/6 at 300 mg, 4/6 at 500 mg, and 5/6 at 680 mg. Vomiting occurred in 1/6 and 4/6 subjects at 500 mg and 680 mg, respectively. SAR302503 was absorbed with a median tmax of 1.8 to 3.0 hrs. Mean t1/2z ranged from 62.1 to 78.2 hrs at the 300 to 680 mg doses with sampling to 168 hrs. SAR302503 exposure increased in a greater than dose-proportional manner, with a 68-fold increase in dose resulting in 473- and 989-fold increases in Cmax and AUClast, respectively. Dose had no effect on t1/2z. Subjects receiving a single dose of 300, 500, or 680 mg of SAR302503, demonstrated a reduction in pSTAT3 levels, indicative of JAK2 inhibition. The mean pSTAT3 levels 3 hrs postdose were 76%, 50%, and 42% of predose levels in the 300, 500, and 680 mg groups, respectively. The relationship between SAR302503 plasma concentration and pSTAT3 inhibition was described by an inhibitory effect sigmoid maximum effect Emax model, with an EC50 of 1230 ng/mL. Conclusion: Adverse events associated with SAR302503 treatment were mild and primarily gastrointestinal. Following administration of single daily oral doses, SAR302503 exposure appeared to increase in a greater than dose-proportional manner. pSTAT3 inhibition was observed at doses of 300 mg and above. Citation Format: Meng Zhang, Christine R. Xu, Elias Shamiyeh, Feng Liu, Jianyun Yin, Lisa L. von Moltke, William B. Smith. A randomized, placebo-controlled study of the tolerability, pharmacokinetics, and pharmacodynamics of the oral JAK2 inhibitor SAR302503 in healthy volunteers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3364. doi:10.1158/1538-7445.AM2013-3364
Radiotherapy is one of the most important treatments for high-grade glioma (HGG), but the best way to delineate the target areas for radiotherapy remains controversial, so our aim was to compare the dosimetric differences in radiation treatment plans generated based on the European Organization for Research and Treatment of Cancer (EORTC) and National Research Group (NRG) consensus to provide evidence for optimal target delineation for HGG.We prospectively enrolled 13 patients with a confirmed HGG from our hospital and assessed dosimetric differences in radiotherapy treatment plans generated according to the EORTC and NRG-2019 guidelines. For each patient, two treatment plans were generated. Dosimetric parameters were compared by dose-volume histograms for each plan.The median volume for planning target volume (PTV) of EORTC plans, PTV1 of NRG-2019 plans, and PTV2 of NRG-2019 plans were 336.6 cm3 (range, 161.1-511.5 cm3), 365.3 cm3 (range, 123.4-535.0 cm3), and 263.2 cm3 (range, 116.8-497.7 cm3), respectively. Both treatment plans were found to have similar efficiency and evaluated as acceptable for patient treatment. Both treatment plans showed well conformal index and homogeneity index and were not statistically significantly different (P = 0.397 and P = 0.427, respectively). There was no significant difference in the volume percent of brain irradiated to 30, 46, and 60 Gy according to different target delineations (P = 0.397, P = 0.590, and P = 0.739, respectively). These two plans also showed no significant differences in the doses to the brain stem, optic chiasm, left and right optic nerves, left and right lens, left and right eyes, pituitary, and left and right temporal lobes (P = 0.858, P = 0.858, P = 0.701 and P = 0.794, P = 0.701 and P = 0.427, P = 0.489 and P = 0.898, P = 0.626, and P = 0.942 and P = 0.161, respectively).The NRG-2019 project did not increase the dose of organs at risk (OARs) radiation. This is a significant finding that further lays the groundwork for the application of the NRG-2019 consensus in the treatment of patients with HGGs.The effect of radiotherapy target area and glial fibrillary acidic protein (GFAP) on the prognosis of high-grade glioma and its mechanism, number ChiCTR2100046667. Registered 26 May 2021.
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