Radiotherapy and anti-PD-1/PD-L1 combinations in lung cancer: building better translational research platforms

Abstract

Despite the unheralded success of immune checkpoint blockade in delivering durable responses for some patients with non-small cell lung cancer (NSCLC), the majority of patients do not respond. PD-L1 tumour expression and pre-existing tumour T-cell infiltration have been correlated with improved clinical outcomes to anti-PD-1/anti-PD-L1. However, patients with tumours that are negative for PD-L1 expression can also respond to treatment. Strategies to combine other treatment modalities like radiotherapy with immune checkpoint inhibitors are being investigated as means of improving the response rates to PD-1/PD-L1 antibody blockade. Radiotherapy induces immunogenic changes in cancer cells, can adaptively upregulate tumour cell PD-L1 expression and can improve the efficacy of anti-PD-1/anti-PD-L1 therapy. How we design future clinical trials in NSCLC also depends on practical considerations of delivering these treatment combinations, such as radiotherapy dose, fractionation and field volume, as well as scheduling with immune checkpoint blockade. Here, we review reasons for resistance to anti-PD-1/anti-PD-L1 and how radiotherapy may be utilised in combination with these drugs to enhance their effect by building better translational research platforms.

http://ift.tt/2BB7dSL

Radiotherapy and anti-PD-1/PD-L1 combinations in lung cancer: building better translational research platforms

Abstract

Despite the unheralded success of immune checkpoint blockade in delivering durable responses for some patients with non-small cell lung cancer (NSCLC), the majority of patients do not respond. PD-L1 tumour expression and pre-existing tumour T-cell infiltration have been correlated with improved clinical outcomes to anti-PD-1/anti-PD-L1. However, patients with tumours that are negative for PD-L1 expression can also respond to treatment. Strategies to combine other treatment modalities like radiotherapy with immune checkpoint inhibitors are being investigated as means of improving the response rates to PD-1/PD-L1 antibody blockade. Radiotherapy induces immunogenic changes in cancer cells, can adaptively upregulate tumour cell PD-L1 expression and can improve the efficacy of anti-PD-1/anti-PD-L1 therapy. How we design future clinical trials in NSCLC also depends on practical considerations of delivering these treatment combinations, such as radiotherapy dose, fractionation and field volume, as well as scheduling with immune checkpoint blockade. Here, we review reasons for resistance to anti-PD-1/anti-PD-L1 and how radiotherapy may be utilised in combination with these drugs to enhance their effect by building better translational research platforms.

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Cooperative Epigenetic Remodeling by TET2 Loss and NRAS Mutation Drives Myeloid Transformation and MEK Inhibitor Sensitivity

Publication date: Available online 21 December 2017
Source:Cancer Cell
Author(s): Hiroyoshi Kunimoto, Cem Meydan, Abbas Nazir, Justin Whitfield, Kaitlyn Shank, Franck Rapaport, Rebecca Maher, Elodie Pronier, Sara C. Meyer, Francine E. Garrett-Bakelman, Martin Tallman, Ari Melnick, Ross L. Levine, Alan H. Shih
Mutations in epigenetic modifiers and signaling factors often co-occur in myeloid malignancies, including TET2 and NRAS mutations. Concurrent Tet2 loss and Nras^G12D expression in hematopoietic cells induced myeloid transformation, with a fully penetrant, lethal chronic myelomonocytic leukemia (CMML), which was serially transplantable. Tet2 loss and Nras mutation cooperatively led to decrease in negative regulators of mitogen-activated protein kinase (MAPK) activation, including Spry2, thereby causing synergistic activation of MAPK signaling by epigenetic silencing. Tet2/Nras double-mutant leukemia showed preferential sensitivity to MAPK kinase (MEK) inhibition in both mouse model and patient samples. These data provide insights into how epigenetic and signaling mutations cooperate in myeloid transformation and provide a rationale for mechanism-based therapy in CMML patients with these high-risk genetic lesions.

Graphical abstract

Teaser

Kunimoto et al. show that concurrent Tet2 loss and Nras^G12D expression in hematopoietic cells induces fully penetrant, lethal chronic myelomonocytic leukemia by decreasing negative regulators of MAPK activation. Mouse and human TET2/NRAS double-mutant leukemia show preferential sensitivity to MEK inhibition.


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via IFTTT

Cooperative Epigenetic Remodeling by TET2 Loss and NRAS Mutation Drives Myeloid Transformation and MEK Inhibitor Sensitivity

Publication date: Available online 21 December 2017
Source:Cancer Cell
Author(s): Hiroyoshi Kunimoto, Cem Meydan, Abbas Nazir, Justin Whitfield, Kaitlyn Shank, Franck Rapaport, Rebecca Maher, Elodie Pronier, Sara C. Meyer, Francine E. Garrett-Bakelman, Martin Tallman, Ari Melnick, Ross L. Levine, Alan H. Shih
Mutations in epigenetic modifiers and signaling factors often co-occur in myeloid malignancies, including TET2 and NRAS mutations. Concurrent Tet2 loss and Nras^G12D expression in hematopoietic cells induced myeloid transformation, with a fully penetrant, lethal chronic myelomonocytic leukemia (CMML), which was serially transplantable. Tet2 loss and Nras mutation cooperatively led to decrease in negative regulators of mitogen-activated protein kinase (MAPK) activation, including Spry2, thereby causing synergistic activation of MAPK signaling by epigenetic silencing. Tet2/Nras double-mutant leukemia showed preferential sensitivity to MAPK kinase (MEK) inhibition in both mouse model and patient samples. These data provide insights into how epigenetic and signaling mutations cooperate in myeloid transformation and provide a rationale for mechanism-based therapy in CMML patients with these high-risk genetic lesions.

Graphical abstract

Teaser

Kunimoto et al. show that concurrent Tet2 loss and Nras^G12D expression in hematopoietic cells induces fully penetrant, lethal chronic myelomonocytic leukemia by decreasing negative regulators of MAPK activation. Mouse and human TET2/NRAS double-mutant leukemia show preferential sensitivity to MEK inhibition.


http://ift.tt/2p9NXGo

Intraoperative Doppler sonogram in pediatric liver transplants: a pictorial review of intraoperative and early postoperative complications

Abstract

A spectrum of vascular complications can be seen in pediatric liver transplant patients, including occlusion and hemodynamically significant narrowing of the vessels that provide inflow to or outflow from the graft. Intraoperative Doppler ultrasound (US) has the potential benefit of identifying vascular complications in pediatric liver transplant patients prior to abdominal closure. Importantly, intraoperative Doppler US can be used as a problem-solving tool in situations such as position-dependent kinking of the portal or hepatic veins, or in suspected vasospasm of the hepatic artery. Furthermore, this technique can be used for real-time reassessment after surgical correction of vascular complications. This pictorial review of intraoperative Doppler US in pediatric liver transplant patients illustrates normal findings and common vascular complications, including examples after surgical correction, in the perioperative period.

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via IFTTT

Intraoperative Doppler sonogram in pediatric liver transplants: a pictorial review of intraoperative and early postoperative complications

Abstract

A spectrum of vascular complications can be seen in pediatric liver transplant patients, including occlusion and hemodynamically significant narrowing of the vessels that provide inflow to or outflow from the graft. Intraoperative Doppler ultrasound (US) has the potential benefit of identifying vascular complications in pediatric liver transplant patients prior to abdominal closure. Importantly, intraoperative Doppler US can be used as a problem-solving tool in situations such as position-dependent kinking of the portal or hepatic veins, or in suspected vasospasm of the hepatic artery. Furthermore, this technique can be used for real-time reassessment after surgical correction of vascular complications. This pictorial review of intraoperative Doppler US in pediatric liver transplant patients illustrates normal findings and common vascular complications, including examples after surgical correction, in the perioperative period.

http://ift.tt/2BNzT7U

Late breast cancer treatment-related symptoms and functioning: associations with physical activity adoption and maintenance during a lifestyle intervention for rural survivors

Abstract

Purpose

Physical activity may be difficult for survivors with poorer functioning following primary treatment. The study examined whether late symptoms of breast cancer treatment impact PA adoption (0–6 months) and maintenance (6–18 months) during a weight management intervention, and whether late symptoms influence PA when accounting for overall functioning.

Methods

Secondary analyses were conducted using a sample of survivors participating in a weight management intervention and who provided valid weight and accelerometer data at baseline and 6 months (N = 176). The Breast Cancer Prevention Trial Symptom Checklist (BCPT) assessed late treatment-related symptoms. SF-12 Physical Component Scale (PCS) and Mental Component Scale (MCS) scores assessed functioning.

Results

Change in bouted moderate to vigorous physical activity (MVPA) min/week from baseline to 6 months was not associated with BCPT scales (all p values > 0.05). When adding SF-12 scores to the model, change in bouted MVPA min/week was significantly associated with the PCS (p = 0.045). Change in MVPA min/week from 6 to 18 months was significantly associated with cognitive symptoms (p = 0.004), but not musculoskeletal or vasomotor symptoms (p values > 0.05). When adding 6-month SF-12 scores to the model, MVPA min/week was significantly associated with PCS (p = 0.001) and MCS (p = 0.028); however, BCPT cognitive problems score became non-significant (p > 0.05).

Conclusions

Poorer physical functioning was associated with lower PA adoption, and poorer mental and physical functioning was associated with lower maintenance of PA, while late symptoms generally were not. Interventionists should consider level of functioning when identifying individual PA goals during weight management interventions.

http://ift.tt/2BXTV29