Real-world treatment patterns in advanced pancreatic neuroendocrine tumors in the era of targeted therapy: perspectives from an academic tertiary center and community oncology practices

Abstract

Pancreatic neuroendocrine tumors (pNETs) are rare, slow-growing cancers. Optimal treatment of advanced pNETs is unclear. The aim of this study was to examine treatment patterns and preferences among an academic tertiary medical center and community-based oncology practices. Retrospective chart review was performed for patients with newly diagnosed locally advanced, metastatic, or unresectable pNET diagnosed between January 2010 and December 2013 at an academic tertiary cancer center [University of California, San Francisco (UCSF)] or a large network of community oncology practices [Altos Solutions' OncoEMR database (ALTOS)]. Fifty-four eligible patients (N _UCSF = 23; N _ALTOS = 31) were identified. Median time to treatment initiation was 1.1 months; median follow-up time was 22.9 months. UCSF patients underwent more lines of therapy than ALTOS patients despite similar follow-up times. UCSF tended toward more invasive treatment than ALTOS. The median time to treatment discontinuation was statistically significantly shorter for patients on chemotherapy than on targeted therapy in the combined UCSF and ALTOS groups (chemotherapy = 2.1 months vs. targeted = 18.6 months, p < 0.001). Treatment patterns and duration for newly diagnosed advanced pNETs vary widely both within and between different practice settings. Further studies are warranted to investigate the significant difference in duration of targeted therapy compared to chemotherapy.

from Cancer via ola Kala on Inoreader http://ift.tt/2of6EEq
via IFTTT

Luteolin induces apoptosis by ROS/ER stress and mitochondrial dysfunction in gliomablastoma

Abstract

Objective

Luteolin, a common dietary flavonoid, induces apoptosis of many types of cancer cells. However, its role in glioblastoma and the potential mechanisms remain unknown. In this research, we studied the molecular mechanisms of the anti-cancer effect of luteolin in glioblastoma cancer cell lines.

Methods

Both U251MG and U87MG human glioblastoma cell lines were tested. Cell growth was assessed by the cell counting kit-8. Cell apoptosis was detected with flow cytometry and caspase-3 immunofluorescence staining. The protein levels of caspase-3/Bax/Bcl-2 and p-PERK/p-eIF2α/ATF4/CHOP/caspase-12 pathway were analyzed using western blots. Reactive oxygen species generation was measured with DCFH-DA staining using flow cytometry. Mitochondrial membrane potential was tested with JC-1 staining. Anti-cancer effect in vivo was measured using tumor xenograft mode in nude mice.

Results

Luteolin induced a lethal endoplasmic reticulum stress response and mitochondrial dysfunction in glioblastoma cells by increasing intracellular reactive oxygen species (ROS) levels. Luteolin induced expression of ER stress-associated proteins, including phosphorylation of PERK, eIF2α, ATF4, CHOP and cleaved-caspase 12. Inhibition of ROS production by anti-oxidant N-acetylcysteine could reverse luteolin-induced ER stress and mitochondrial pathways activation as well as apoptosis. What's more, we also showed the anticancer effect of luteolin in vivo.

Conclusions

Our results suggest that luteolin induces apoptosis through activating ER stress and mitochondrial dysfunction in glioblastoma cell lines and in vivo, which provides the anti-cancer candidate to treat glioblstoma.

http://ift.tt/2omGYYu

Luteolin induces apoptosis by ROS/ER stress and mitochondrial dysfunction in gliomablastoma

Abstract

Objective

Luteolin, a common dietary flavonoid, induces apoptosis of many types of cancer cells. However, its role in glioblastoma and the potential mechanisms remain unknown. In this research, we studied the molecular mechanisms of the anti-cancer effect of luteolin in glioblastoma cancer cell lines.

Methods

Both U251MG and U87MG human glioblastoma cell lines were tested. Cell growth was assessed by the cell counting kit-8. Cell apoptosis was detected with flow cytometry and caspase-3 immunofluorescence staining. The protein levels of caspase-3/Bax/Bcl-2 and p-PERK/p-eIF2α/ATF4/CHOP/caspase-12 pathway were analyzed using western blots. Reactive oxygen species generation was measured with DCFH-DA staining using flow cytometry. Mitochondrial membrane potential was tested with JC-1 staining. Anti-cancer effect in vivo was measured using tumor xenograft mode in nude mice.

Results

Luteolin induced a lethal endoplasmic reticulum stress response and mitochondrial dysfunction in glioblastoma cells by increasing intracellular reactive oxygen species (ROS) levels. Luteolin induced expression of ER stress-associated proteins, including phosphorylation of PERK, eIF2α, ATF4, CHOP and cleaved-caspase 12. Inhibition of ROS production by anti-oxidant N-acetylcysteine could reverse luteolin-induced ER stress and mitochondrial pathways activation as well as apoptosis. What's more, we also showed the anticancer effect of luteolin in vivo.

Conclusions

Our results suggest that luteolin induces apoptosis through activating ER stress and mitochondrial dysfunction in glioblastoma cell lines and in vivo, which provides the anti-cancer candidate to treat glioblstoma.

from Cancer via ola Kala on Inoreader http://ift.tt/2omGYYu
via IFTTT

Evaluating which dose-function metrics are most critical for functional-guided radiotherapy with CT ventilation imaging

Publication date: Available online 8 April 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Austin M. Faught, Tokihiro Yamamoto, Richard Castillo, Edward Castillo, Jingjing Zhang, Moyed Miften, Yevgeniy Vinogradskiy
Purpose4DCT-ventilation imaging is increasingly being used to calculate lung ventilation and implement functional-guided radiotherapy in clinical trials. There has been little exhaustive work evaluating which dose-function metrics should be used for treatment planning and plan evaluation. The purpose of our study was to evaluate which dose-function metrics best predict for radiation pneumonitis (RP).Methods and MaterialsSeventy lung cancer patients with 4DCT imaging and pneumonitis grading were used. Pre-treatment 4DCTs of each patient were used to calculate ventilation images. We evaluated 3 types of dose function metrics that combined that patient's 4DCT-ventilation image and treatment planning dose distribution: 1) structure-based approaches 2) image-based approaches using the dose-function histogram (DFH) and 3) non-linear weighting schemes. Log-likelihood methods were used to generate normal tissue complication probability (NTCP) models predicting grade 3+ pneumonitis for all dose-function schemes. The area under the curve (AUC) was used to assess the predictive power of the models. All techniques were compared to NTCP models based on traditional, total lung dose metrics.ResultsThe most predictive models were structure-based approaches that focused on the volume of functional lung receiving ≥20Gy (AUC=0.70). Probability of grade 3+ RP of 20% and 10% correspond to V20Gy to the functional sub-volumes of 26.8% and 9.3%, respectively. Imaging-based analysis with the DFH and non-linear weighted ventilation values yielded AUCs of 0.66 and 0.67, respectively, when evaluating the percentage of functionality receiving ≥20Gy. All dose-function metrics outperformed the traditional dose metrics (mean lung dose, AUC=0.55).ConclusionA full range of dose-function metrics and functional thresholds were examined. The calculated AUC values for the most predictive functional models occupied a narrow range (0.66-0.70) and all demonstrated notable improvements over AUC from traditional lung dose metrics (0.55). Identifying the combinations most predictive of grade 3+ RP provides valuable data to inform the functional-guided radiotherapy process.

Teaser

We performed a retrospective analysis of 70 lung cancer patients with 4DCT images to assess which dose-function metrics are most predictive of clinical radiation pneumonitis and should be used in functional-guided radiotherapy. Normal tissue complication probability models were developed based on standard lung dose metrics and four additional functional schemes that considered lung function as determined from 4DCT ventilation imaging. Results provide valuable data in the guidance of prospective clinical trials in functional-guided radiotherapy.


http://ift.tt/2nuj8Lb

PERK signalling pathway mediates single prolonged stress-induced dysfunction of medial prefrontal cortex neurons

Abstract

Post-traumatic stress disorder (PTSD) is characterized with abnormal learning and memory. Impairments in learning and memory are closely associated with apoptosis in the medial prefrontal cortex (mPFC). We previously examined the endoplasmic reticulum (ER) stress was involved in the apoptosis in the mPFC of PTSD. The PERK pathway plays the important role in the ER stress-induced apoptosis. The aim of the present study was to explore the role of PERK pathway in neuronal apoptosis in the mPFC of rat models of PTSD. We used the single prolonged stress (SPS) to mimic PTSD in rats and studied the effects of the PERK pathway in mPFC. Learning and memory behavior were examined by Morris water maze and novel object recognition tests. Apoptosis in mPFC was detected by TUNEL staining. Our results showed decreased learning memory and increased apoptosis of mPFC neurons in rats exposed to SPS. SPS exposure upregulate mRNA expressions of PERK, p-PERK, eIF2α, p-eIF2α, nuclear ATF4 and C/EBP-homologous protein (CHOP) in mPFC neurons, but the protein levels of these molecules showed difference in magnitude and time course. GSK2606414 (an antagonist of PERK) treatment successfully reversed the above changes. These results suggested that the PERK pathway mediated SPS-induced neural apoptosis in the mPFC. These findings will be helpful in understanding mPFC-related pathogenesis of PTSD.

http://ift.tt/2oaV2lR

Rivaroxaban as an effective alternative to warfarin in a patient with atrial fibrillation, thrombophilia, and left atrial appendage thrombus: a case report

Atrial fibrillation is the most common cardiac arrhythmia. It is responsible for up to 20% of all ischemic strokes. Rate control and anticoagulation are crucial for atrial fibrillation management and stroke pr...

http://ift.tt/2odgE0Y

Background noise lowers the performance of anaesthesiology residents' clinical reasoning when measured by script concordance: A prospective randomised crossover volunteer study.

BACKGROUND: Noise, which is omnipresent in operating rooms and ICUs, may have a negative impact not only patients but also on the concentration of and communication between clinical staff. OBJECTIVE: The present study attempted to evaluate the impact of noise on the performance of anaesthesiology residents' clinical reasoning. Changes in clinical reasoning were measured by script concordance tests (SCTs). DESIGN: This was a prospective, randomised and crossover study. SETTING: Single centre at Rouen University Hospital in April 2014. POPULATION: All year 1 to 4 residents enrolled in the anaesthesiology training programme were included. INTERVENTION: Performance was assessed using a 56-item SCT. Two resident groups were formed, and each was exposed to both quiet and noisy atmospheres during SCT assessment. Group A did the first part of the assessment (28 SCT) in a quiet atmosphere and the second part (28 SCT) in a noisy atmosphere. Group B did the same in reverse order. MAIN OUTCOME MEASURES: The primary outcome of this study was residents' performance as measured by SCT, with and without noise (mean of 100 points 95% confidence interval). RESULTS: Forty-two residents were included. Residents' performance, measured by SCT, was weaker in a noisy environment than in a quiet environment [59.0 (56.0 to 62.0) vs 62.8 (60.8 to 64.9), P = 0.04]. This difference lessened as medical training advanced, as this difference in performance in noisy vs quiet environments was not observed in year 3 and 4 residents [62.9 (59.2 to 66.5) vs 64.0 (61.9 to 66.1), P = 0.60], whereas it was higher for year 1 and 2 residents [54.8 (50.6 to 59.1) vs 61.5 (57.9 to 65.1), P = 0.02]. CONCLUSION: Our study suggests that noise affects clinical reasoning of anaesthesiology residents especially junior residents when measured by SCT. This observation supports the hypothesis that noise should be prevented in operating rooms especially when junior residents are providing care. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://ift.tt/OBJ4xP (C) 2017 European Society of Anaesthesiology

http://ift.tt/2okvgO5