Stent-assisted coiling of a ruptured vertebrobasilar junction aneurysm via direct vertebral artery puncture

A 78-year-old patient was admitted with subarachnoid hemorrhage caused by rupture of a broad-based vertebrobasilar junction aneurysm. Direct endovascular access to the vertebrobasilar circulation was not possible due to chronic occlusion of the proximal dominant left vertebral artery (VA), hypoplastic right VA and posterior communicating arteries. The distal cervical left VA was reconstituted by muscular branches of the ascending cervical artery. Therefore, endovascular access was gained by direct percutaneous VA puncture guided by a roadmap-controlled anterior approach at the level of C5 proximally to the main reconstituting collateral feeders. Successful endovascular treatment of the aneurysm was performed by stent-assisted coiling. Closure of the puncture site at the cervical VA level was achieved by occluding the proximal part of the VA with coils. The post-interventional clinical course was uneventful; early post-interventional CT showed no evidence of cervical hematoma.

http://ift.tt/2wmahLY

Intrapartum assessment of fetal well-being

1A012A043J02

http://ift.tt/2k2Dfi4

Molecular Tumor Boards: Current Practice and Future Needs

Abstract

Background

due to rapid technical advances, steeply declining sequencing costs, and the ever-increasing number of targeted therapies, it can be expected that extensive tumor sequencing such as Whole Exome- and -Genome Sequencing will soon be applied in standard care. Clinicians will thus be confronted with increasingly complex genetic information and multiple test-platforms to choose from. General medical training, meanwhile, can hardly keep up with the pace of innovation. Consequently, there is a rapidly growing gap between clinical knowledge and genetic potential in cancer care. Multidisciplinary Molecular Tumor Boards (MTBs) have been suggested as a means to address this disparity, but shared experiences are scarce in literature and no quality requirements or guidelines have been published to date.

Methods

based on literature review, a survey amongst hospitals in the Netherlands, and our own experience with the establishment of a nationally operating MTB, this paper evaluates current knowledge and unmet needs, and lays out a strategy for successful MTB implementation.

Results

having access to an MTB can improve and increase the application of genetics-guided cancer care. In our survey, however, less than 50% of hospitals and only 5% of non-academic hospitals had access to an MTB. In addition, current MTBs vary widely in terms of composition, tasks, tools and workflow. This may not only lead to variation in quality of care, but also hinders data sharing and thus creation of an effective learning community.

Conclusions

this paper acknowledges a leading role for MTBs to govern (extensive) tumor sequencing into daily practice, and proposes three basic necessities for successful MTB implementation: (i) global harmonization in cancer sequencing practices and procedures, (ii) minimal member- and operational requirements, and (iii) an appropriate unsolicited findings policy. Meeting these prerequisites would not only optimize MTB functioning, but also improve general interpretation and application of genomics-guided cancer care.

http://ift.tt/2yIHz9x

Molecular Tumor Boards: Current Practice and Future Needs

Abstract

Background

due to rapid technical advances, steeply declining sequencing costs, and the ever-increasing number of targeted therapies, it can be expected that extensive tumor sequencing such as Whole Exome- and -Genome Sequencing will soon be applied in standard care. Clinicians will thus be confronted with increasingly complex genetic information and multiple test-platforms to choose from. General medical training, meanwhile, can hardly keep up with the pace of innovation. Consequently, there is a rapidly growing gap between clinical knowledge and genetic potential in cancer care. Multidisciplinary Molecular Tumor Boards (MTBs) have been suggested as a means to address this disparity, but shared experiences are scarce in literature and no quality requirements or guidelines have been published to date.

Methods

based on literature review, a survey amongst hospitals in the Netherlands, and our own experience with the establishment of a nationally operating MTB, this paper evaluates current knowledge and unmet needs, and lays out a strategy for successful MTB implementation.

Results

having access to an MTB can improve and increase the application of genetics-guided cancer care. In our survey, however, less than 50% of hospitals and only 5% of non-academic hospitals had access to an MTB. In addition, current MTBs vary widely in terms of composition, tasks, tools and workflow. This may not only lead to variation in quality of care, but also hinders data sharing and thus creation of an effective learning community.

Conclusions

this paper acknowledges a leading role for MTBs to govern (extensive) tumor sequencing into daily practice, and proposes three basic necessities for successful MTB implementation: (i) global harmonization in cancer sequencing practices and procedures, (ii) minimal member- and operational requirements, and (iii) an appropriate unsolicited findings policy. Meeting these prerequisites would not only optimize MTB functioning, but also improve general interpretation and application of genomics-guided cancer care.

from Cancer via ola Kala on Inoreader http://ift.tt/2yIHz9x
via IFTTT

Brain functional connectivity differentiates dexmedetomidine from propofol and natural sleep

Abstract

Background.

We used functional connectivity measures from brain resting state functional magnetic resonance imaging to identify human neural correlates of sedation with dexmedetomidine or propofol and their similarities with natural sleep.

Methods.

Connectivity within the resting state networks that are proposed to sustain consciousness generation was compared between deep non-rapid-eye-movement (N3) sleep, dexmedetomidine sedation, and propofol sedation in volunteers who became unresponsive to verbal command. A newly acquired dexmedetomidine dataset was compared with our previously published propofol and N3 sleep datasets.

Results.

In all three unresponsive states (dexmedetomidine sedation, propofol sedation, and N3 sleep), within-network functional connectivity, including thalamic functional connectivity in the higher-order (default mode, executive control, and salience) networks, was significantly reduced as compared with the wake state. Thalamic functional connectivity was not reduced for unresponsive states within lower-order (auditory, sensorimotor, and visual) networks. Voxel-wise statistical comparisons between the different unresponsive states revealed that thalamic functional connectivity with the medial prefrontal/anterior cingulate cortex and with the mesopontine area was reduced least during dexmedetomidine-induced unresponsiveness and most during propofol-induced unresponsiveness. The reduction seen during N3 sleep was intermediate between those of dexmedetomidine and propofol.

Conclusions.

Thalamic connectivity with key nodes of arousal and saliency detection networks was relatively preserved during N3 sleep and dexmedetomidine-induced unresponsiveness as compared to propofol. These network effects may explain the rapid recovery of oriented responsiveness to external stimulation seen under dexmedetomidine sedation.

Trial registry number.

Committee number: 'Comité d'Ethique Hospitalo-Facultaire Universitaire de Liège' (707); EudraCT number: 2012-003562-40; internal reference: 20121/135; accepted on August 31, 2012; Chair: Prof G. Rorive. As it was considered a phase I clinical trial, this protocol does not appear on the EudraCT public website.

http://ift.tt/2yuexJP

Crizotinib targets in glioblastoma stem cells

Abstract

Glioblastoma stem cells (GSCs) are believed to be involved in the mechanisms of tumor resistance, therapeutic failures, and recurrences after conventional glioblastoma therapy. Therefore, elimination of GSCs might be a prerequisite for the development of successful therapeutic strategies. ALK, ROS1, and MET are targeted by Crizotinib, a tyrosine kinase inhibitor which has been approved for treatment of ALK-rearranged non–small-cell lung cancer. In this study we investigated ALK, ROS1, and MET status in nine glioblastoma stem cell lines and tumors from which they arise. Fluorescent in situ hybridization (FISH), Sanger's direct sequencing, and immunohistochemistry were used to screen genomic rearrangements (or amplifications), genomic mutations, and protein expression, respectively. The immunohistochemical and FISH studies revealed no significant dysregulation of ROS1 in GSCs and associated tumors. Neither amplification nor polysomy of ALK was observed in GSC, but weak overexpression was detected by IHC in three of nine GSCs. Similarly, no MET amplification was found by FISH but three GSCs presented significant immunohistochemical staining. No ALK or MET mutation was found by Sanger's direct sequencing. In this study, we show no molecular rearrangement of ALK, ROS1, and MET that would lead us not to propose, as a valid strategy, the use of crizotinib to eradicate GSCs. However, MET was overexpressed in all GSCs with mesenchymal subtype and three GSCs presented an overexpression of ALK. Therefore, our study corroborates the idea that MET and ALK may assume a role in the tumorigenicity of GSC.

Tissue and stem cells microarrays from nine glioblastomas samples were used to evaluate expression and chromosomal abnormalities of ALK, ROS1, and MET. No molecular rearrangement of these three important genes was observed but rather an overexpression of ALK and MET in some of the glioblastoma stem cell samples, supporting the role of these two genes in tumorigenicity.

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

Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells

Abstract

Malignant pleural mesothelioma (MPM), an asbestos-related occupational disease, is an aggressive and incurable tumor of the thoracic cavity. Despite recent advances in MPM treatment, overall survival of patients with MPM is very low. Recent studies have implicated that PI3K/Akt signaling is involved in MPM cell survival and development. To investigate the effects of Akt inhibitors on MPM cell survival, we examined the effects of nine selective Akt inhibitors, namely, afuresertib, Akti-1/2, AZD5363, GSK690693, ipatasertib, MK-2206, perifosine, PHT-427, and TIC10, on six MPM cell lines, namely, ACC-MESO-4, Y-MESO-8A, MSTO-211H, NCI-H28, NCI-H290, and NCI-H2052, and a normal mesothelial cell line MeT-5A. Comparison of IC₅₀ values of the Akt inhibitors showed that afuresertib, an ATP-competitive specific Akt inhibitor, exerted tumor-specific effects on MPM cells. Afuresertib significantly increased caspase-3 and caspase-7 activities and apoptotic cell number among ACC-MESO-4 and MSTO-211H cells. Moreover, afuresertib strongly arrested the cell cycle in the G₁ phase. Western blotting analysis showed that afuresertib increased the expression of p21^WAF1/CIP1 and decreased the phosphorylation of Akt substrates, including GSK-3β and FOXO family proteins. These results suggest that afuresertib-induced p21 expression promotes G₁ phase arrest by inducing FOXO activity. Furthermore, afuresertib significantly enhanced cisplatin-induced cytotoxicity. Interestingly, results of gene set enrichment analysis showed that afuresertib modulated the expression E2F1 and MYC, which are associated with fibroblast core serum response. Together, these results suggest that afuresertib is a useful anticancer drug for treating patients with MPM.

Novel ATP-competitive Akt inhibitor afuresertib exerts tumor-specific antiproliferative effect on MPM cells. Afuresertib significantly enhanced cisplatin-induced cytotoxicity, suggesting that afuresertib is a useful anticancer drug for treating patients with MPM.

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

Bone marrow biopsy superiority over PET/CT in predicting progression-free survival in a homogeneously-treated cohort of diffuse large B-cell lymphoma

Abstract

Several studies have reported uneven results when evaluating the prognostic value of bone marrow biopsy (BMB) and PET/CT as part of the staging of diffuse large B-cell lymphoma (DLBCL). The heterogeneity of the inclusion criteria and not taking into account selection and collinearity biases in the analysis models might explain part of these discrepancies. To address this issue we have carried a retrospective multicenter study including 268 DLBCL patients with a BMB and a PET/CT available at diagnosis where we estimated both the prognosis impact and the diagnostic accuracy of each technique. Only patients treated with R-CHOP/21 as first line (n = 203) were included in the survival analysis. With a median follow-up of 25 months the estimated 3-year progression-free survival (PFS) and overall survival (OS) were 76.3% and 82.7% respectively. In a multivariate analysis designed to avoid a collinearity bias with IPI categories, BMB-BMI [bone marrow involvement](+) (HR: 3.6) and ECOG PS > 1 (HR: 2.9) were independently associated with a shorter PFS and three factors, age >60 years old (HR: 2.4), ECOG PS >1 (HR: 2.4), and abnormally elevated B2-microglobulin levels (HR: 2.2) were independently associated with a shorter OS. In our DLBCL cohort, treated with a uniform first-line chemotherapy regimen, BMI by BMB complemented performance status in predicting those patients with a higher risk for relapse or progression. In this cohort BMI by PET/CT could not independently predict a shorter PFS and/or OS.

Bone marrow involvement by biopsy complemented performance status in predicting those patients with a higher risk for relapse or progression. In this cohort, bone marrow involvement by PET/CT could not independently predict a shorter PFS and/or OS.

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

Crizotinib targets in glioblastoma stem cells

Abstract

Glioblastoma stem cells (GSCs) are believed to be involved in the mechanisms of tumor resistance, therapeutic failures, and recurrences after conventional glioblastoma therapy. Therefore, elimination of GSCs might be a prerequisite for the development of successful therapeutic strategies. ALK, ROS1, and MET are targeted by Crizotinib, a tyrosine kinase inhibitor which has been approved for treatment of ALK-rearranged non–small-cell lung cancer. In this study we investigated ALK, ROS1, and MET status in nine glioblastoma stem cell lines and tumors from which they arise. Fluorescent in situ hybridization (FISH), Sanger's direct sequencing, and immunohistochemistry were used to screen genomic rearrangements (or amplifications), genomic mutations, and protein expression, respectively. The immunohistochemical and FISH studies revealed no significant dysregulation of ROS1 in GSCs and associated tumors. Neither amplification nor polysomy of ALK was observed in GSC, but weak overexpression was detected by IHC in three of nine GSCs. Similarly, no MET amplification was found by FISH but three GSCs presented significant immunohistochemical staining. No ALK or MET mutation was found by Sanger's direct sequencing. In this study, we show no molecular rearrangement of ALK, ROS1, and MET that would lead us not to propose, as a valid strategy, the use of crizotinib to eradicate GSCs. However, MET was overexpressed in all GSCs with mesenchymal subtype and three GSCs presented an overexpression of ALK. Therefore, our study corroborates the idea that MET and ALK may assume a role in the tumorigenicity of GSC.

Tissue and stem cells microarrays from nine glioblastomas samples were used to evaluate expression and chromosomal abnormalities of ALK, ROS1, and MET. No molecular rearrangement of these three important genes was observed but rather an overexpression of ALK and MET in some of the glioblastoma stem cell samples, supporting the role of these two genes in tumorigenicity.

http://ift.tt/2xCyVcy

Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells

Abstract

Malignant pleural mesothelioma (MPM), an asbestos-related occupational disease, is an aggressive and incurable tumor of the thoracic cavity. Despite recent advances in MPM treatment, overall survival of patients with MPM is very low. Recent studies have implicated that PI3K/Akt signaling is involved in MPM cell survival and development. To investigate the effects of Akt inhibitors on MPM cell survival, we examined the effects of nine selective Akt inhibitors, namely, afuresertib, Akti-1/2, AZD5363, GSK690693, ipatasertib, MK-2206, perifosine, PHT-427, and TIC10, on six MPM cell lines, namely, ACC-MESO-4, Y-MESO-8A, MSTO-211H, NCI-H28, NCI-H290, and NCI-H2052, and a normal mesothelial cell line MeT-5A. Comparison of IC₅₀ values of the Akt inhibitors showed that afuresertib, an ATP-competitive specific Akt inhibitor, exerted tumor-specific effects on MPM cells. Afuresertib significantly increased caspase-3 and caspase-7 activities and apoptotic cell number among ACC-MESO-4 and MSTO-211H cells. Moreover, afuresertib strongly arrested the cell cycle in the G₁ phase. Western blotting analysis showed that afuresertib increased the expression of p21^WAF1/CIP1 and decreased the phosphorylation of Akt substrates, including GSK-3β and FOXO family proteins. These results suggest that afuresertib-induced p21 expression promotes G₁ phase arrest by inducing FOXO activity. Furthermore, afuresertib significantly enhanced cisplatin-induced cytotoxicity. Interestingly, results of gene set enrichment analysis showed that afuresertib modulated the expression E2F1 and MYC, which are associated with fibroblast core serum response. Together, these results suggest that afuresertib is a useful anticancer drug for treating patients with MPM.

Novel ATP-competitive Akt inhibitor afuresertib exerts tumor-specific antiproliferative effect on MPM cells. Afuresertib significantly enhanced cisplatin-induced cytotoxicity, suggesting that afuresertib is a useful anticancer drug for treating patients with MPM.

http://ift.tt/2wXwjZR

Bone marrow biopsy superiority over PET/CT in predicting progression-free survival in a homogeneously-treated cohort of diffuse large B-cell lymphoma

Abstract

Several studies have reported uneven results when evaluating the prognostic value of bone marrow biopsy (BMB) and PET/CT as part of the staging of diffuse large B-cell lymphoma (DLBCL). The heterogeneity of the inclusion criteria and not taking into account selection and collinearity biases in the analysis models might explain part of these discrepancies. To address this issue we have carried a retrospective multicenter study including 268 DLBCL patients with a BMB and a PET/CT available at diagnosis where we estimated both the prognosis impact and the diagnostic accuracy of each technique. Only patients treated with R-CHOP/21 as first line (n = 203) were included in the survival analysis. With a median follow-up of 25 months the estimated 3-year progression-free survival (PFS) and overall survival (OS) were 76.3% and 82.7% respectively. In a multivariate analysis designed to avoid a collinearity bias with IPI categories, BMB-BMI [bone marrow involvement](+) (HR: 3.6) and ECOG PS > 1 (HR: 2.9) were independently associated with a shorter PFS and three factors, age >60 years old (HR: 2.4), ECOG PS >1 (HR: 2.4), and abnormally elevated B2-microglobulin levels (HR: 2.2) were independently associated with a shorter OS. In our DLBCL cohort, treated with a uniform first-line chemotherapy regimen, BMI by BMB complemented performance status in predicting those patients with a higher risk for relapse or progression. In this cohort BMI by PET/CT could not independently predict a shorter PFS and/or OS.

Bone marrow involvement by biopsy complemented performance status in predicting those patients with a higher risk for relapse or progression. In this cohort, bone marrow involvement by PET/CT could not independently predict a shorter PFS and/or OS.

http://ift.tt/2xCvNNZ

Identification of MEK162 as a radiosensitizer for the treatment of glioblastoma

Glioblastoma (GBM) is a highly aggressive and lethal brain cancer type. PI3K and MAPK inhibitors have been studied pre-clinically in GBM as monotherapy, but not in combination with radiotherapy, which is a key component of the current standard treatment of GBM. In our study, GBM cell lines and patient representative primary cultures were grown as multicellular spheroids. Spheroids were treated with a panel of small molecule drugs including MK2206, RAD001, BEZ235, MLN0128 and MEK162, alone and in combination with irradiation. Following treatment, spheroid growth parameters (growth rate, volume reduction and time to regrow), cell cycle distribution and expression of key target proteins were evaluated. In vivo, the effect of irradiation (3 x 2 Gy) without or with MEK162 (50 mg/kg) was studied in orthotopic GBM8 brain tumor xenografts with endpoints tumor growth and animal survival. The MAPK targeting agent MEK162 was found to enhance the effect of irradiation as demonstrated by growth inhibition of spheroids. MEK162 down-regulated and dephosphorylated the cell cycle checkpoint proteins CDK1/CDK2/WEE1 and DNA damage response proteins p-ATM/p-CHK2. When combined with radiation this led to a prolonged DNA damage signal. In vivo data on tumor bearing animals demonstrated a significantly reduced growth rate, increased growth delay and prolonged survival time. In addition, RNA expression of responsive cell cultures correlated to mesenchymal stratification of patient expression data. In conclusion, the MAPK inhibitor MEK162 was identified as radiosensitizer in GBM spheroids in vitro and in orthotopic GBM xenografts in vivo. The data are supportive for implementation of this targeted agent in an early phase clinical study in GBM patients.

http://ift.tt/2wlXbyi

Pathway-enriched gene signature associated with 53BP1 response to PARP inhibition in triple-negative breast cancer

Treatment of patients with triple negative (ER-negative, PR-negative, HER2-negative) breast cancer remains a challenge. Although PARP inhibitors are being evaluated in clinical trials, biomarkers are needed to identify patients that will most benefit from anti-PARP therapy. We determined the response of three PARP inhibitors: veliparib, olaparib, and talazoparib in a panel of eight triple-negative breast cancer cell lines. Therapeutic responses and cellular phenotypes were elucidated using high-content imaging and quantitative immunofluorescence to assess markers of DNA damage (53BP1) and apoptosis (cleaved-PARP). We determined the pharmacodynamic changes in percentage of cells positive for 53BP1, mean number of 53BP1 foci per cell, and percentage of cells positive for cleaved-PARP. Inspired by traditional dose-response measures of cell viability, an EC50 value was calculated for each cellular phenotype for each PARP inhibitor. The EC50 values for both 53BP1 metrics strongly correlated with IC50 values for each PARP inhibitor. Pathway enrichment analysis identified a set of DNA repair and cell cycle associated genes that were associated with 53BP1 response following PARP inhibition. The overall accuracy of our 63 gene set in predicting response to olaparib in seven breast cancer patient-derived xenograft tumors was 86%. In triple-negative breast cancer patients not treated with anti-PARP therapy, the predicted response rate of our gene signature was 45%. These results indicate that 53BP1 is a biomarker of response to anti-PARP therapy in the laboratory, and our DNA damage response gene signature may be used to identify patients who are most likely to respond to PARP inhibition.

http://ift.tt/2xCAtmU

CRISPR genome-wide screening identifies dependence on the proteasome subunit PSMC6 for Bortezomib sensitivity in multiple myeloma

Bortezomib (BTZ) is highly effective in the treatment of Multiple Myeloma (MM), however emergent drug resistance is common. Consequently, we employed CRISPR targeting 19,052 human genes to identify unbiased targets that contribute to BTZ resistance. Specifically, we engineered an RPMI8226 MM cell line to express Cas9 and a lentiviral-vector CRISPR library and cultured derived cells in doses of BTZ lethal to parental cells. Sequencing was performed on surviving cells to identify inactivated genes responsible for drug resistance. From two independent whole genome screens, we selected 31 candidate genes and constructed a second CRISPR sgRNA library, specifically targeting each of these 31 genes with four sgRNAs. After secondary screening for BTZ resistance, the top 20 "resistance" genes were selected for individual validation. Of these 20 targets the proteasome regulatory subunit PSMC6 was the only gene validated to reproducibly confer BTZ resistance. We confirmed that inhibition of chymotrypsin-like proteasome activity by BTZ was significantly reduced in cells lacking PSMC6. We individually investigated other members of the PSMC group (PSMC1 to 5) and found that deficiency in each of those subunits also imparts BTZ resistance. We found 36 mutations in 19S proteasome subunits out of 895 patients in the IA10 release of the CoMMapss study (http://ift.tt/2xBOiSL). Our findings demonstrate that the PSMC6 subunit is the most prominent target required for BTZ sensitivity in MM cells and should be examined in drug refractory populations.

http://ift.tt/2wlVxwr

Procaine and Local Anesthetic Toxicity: A Collaboration Between the Clinical and Basic Sciences.

In 1924, the Therapeutic Research Committee of the American Medical Association appointed a special committee to investigate deaths following the administration of local anesthetics. The Committee for the Study of Toxic Effects of Local Anesthetics found procaine, although a safer clinical alternative to cocaine, was capable of causing death when large doses were injected into tissues and advised that it should be used with caution. This article describes a collaboration beginning in 1928 between Dr John Lundy of the Mayo Clinic and Dr Robert Isenberger of the University of Kansas, which arose from a controversy surrounding systemic adverse reactions to procaine. Isenberger then traveled to the Mayo Clinic to conduct research on various procaine local and spinal anesthesia doses and sodium amytal's protective effect against procaine-induced toxicity. Lundy and Isenberger's work would add to the ongoing discovery of systemic reactions to local anesthetics. Copyright (C) 2017 by American Society of Regional Anesthesia and Pain Medicine.

http://ift.tt/2wm2GNy

Impact of Regional Anesthesia on Recurrence, Metastasis, and Immune Response in Breast Cancer Surgery: A Systematic Review of the Literature.

Background and Objectives: The perioperative period is critical in the long-term prognosis of breast cancer patients. The use of regional anesthesia, such as paravertebral block (PVB), could be associated with improvements in long-term survival after breast cancer surgery by modulating the inflammatory and immune response associated with the surgical trauma, reducing opioid and general anesthetic consumption, and promoting cancer cells death by a direct effect of local anesthetics. Methods: A systematic literature search was conducted for studies of patients who received PVB for breast cancer surgery. The Jadad score and Ottawa-Newcastle scale were used to assess the methodological quality of randomized controlled trial and observational retrospective studies, respectively. Only high-quality studies were considered for meta-analysis. The selected studies were divided into 3 groups to determine the impact of PVB on (a) recurrence and survival, (b) humoral response, and (c) cellular immune response. Results: We identified 467 relevant studies; 121 of them underwent title and abstract review, 107 were excluded, and 15 studies were selected for full text reading and quality assessment. A meta-analysis was not conducted because of low-quality studies and lack of uniform definition among primary outcomes. Thus, a systematic review of the current evidence was performed. Conclusions: Our study indicates that there are no data to support or refute the use of PVB for reduction of cancer recurrence or improvement in cancer-related survival. However, PVB use is associated with lower levels of inflammation and a better immune response in comparison with general anesthesia and opioid-based analgesia. Copyright (C) 2017 by American Society of Regional Anesthesia and Pain Medicine.

http://ift.tt/2xDAdUL

Identification of MEK162 as a radiosensitizer for the treatment of glioblastoma

Glioblastoma (GBM) is a highly aggressive and lethal brain cancer type. PI3K and MAPK inhibitors have been studied pre-clinically in GBM as monotherapy, but not in combination with radiotherapy, which is a key component of the current standard treatment of GBM. In our study, GBM cell lines and patient representative primary cultures were grown as multicellular spheroids. Spheroids were treated with a panel of small molecule drugs including MK2206, RAD001, BEZ235, MLN0128 and MEK162, alone and in combination with irradiation. Following treatment, spheroid growth parameters (growth rate, volume reduction and time to regrow), cell cycle distribution and expression of key target proteins were evaluated. In vivo, the effect of irradiation (3 x 2 Gy) without or with MEK162 (50 mg/kg) was studied in orthotopic GBM8 brain tumor xenografts with endpoints tumor growth and animal survival. The MAPK targeting agent MEK162 was found to enhance the effect of irradiation as demonstrated by growth inhibition of spheroids. MEK162 down-regulated and dephosphorylated the cell cycle checkpoint proteins CDK1/CDK2/WEE1 and DNA damage response proteins p-ATM/p-CHK2. When combined with radiation this led to a prolonged DNA damage signal. In vivo data on tumor bearing animals demonstrated a significantly reduced growth rate, increased growth delay and prolonged survival time. In addition, RNA expression of responsive cell cultures correlated to mesenchymal stratification of patient expression data. In conclusion, the MAPK inhibitor MEK162 was identified as radiosensitizer in GBM spheroids in vitro and in orthotopic GBM xenografts in vivo. The data are supportive for implementation of this targeted agent in an early phase clinical study in GBM patients.

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

Pathway-enriched gene signature associated with 53BP1 response to PARP inhibition in triple-negative breast cancer

Treatment of patients with triple negative (ER-negative, PR-negative, HER2-negative) breast cancer remains a challenge. Although PARP inhibitors are being evaluated in clinical trials, biomarkers are needed to identify patients that will most benefit from anti-PARP therapy. We determined the response of three PARP inhibitors: veliparib, olaparib, and talazoparib in a panel of eight triple-negative breast cancer cell lines. Therapeutic responses and cellular phenotypes were elucidated using high-content imaging and quantitative immunofluorescence to assess markers of DNA damage (53BP1) and apoptosis (cleaved-PARP). We determined the pharmacodynamic changes in percentage of cells positive for 53BP1, mean number of 53BP1 foci per cell, and percentage of cells positive for cleaved-PARP. Inspired by traditional dose-response measures of cell viability, an EC50 value was calculated for each cellular phenotype for each PARP inhibitor. The EC50 values for both 53BP1 metrics strongly correlated with IC50 values for each PARP inhibitor. Pathway enrichment analysis identified a set of DNA repair and cell cycle associated genes that were associated with 53BP1 response following PARP inhibition. The overall accuracy of our 63 gene set in predicting response to olaparib in seven breast cancer patient-derived xenograft tumors was 86%. In triple-negative breast cancer patients not treated with anti-PARP therapy, the predicted response rate of our gene signature was 45%. These results indicate that 53BP1 is a biomarker of response to anti-PARP therapy in the laboratory, and our DNA damage response gene signature may be used to identify patients who are most likely to respond to PARP inhibition.

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

CRISPR genome-wide screening identifies dependence on the proteasome subunit PSMC6 for Bortezomib sensitivity in multiple myeloma

Bortezomib (BTZ) is highly effective in the treatment of Multiple Myeloma (MM), however emergent drug resistance is common. Consequently, we employed CRISPR targeting 19,052 human genes to identify unbiased targets that contribute to BTZ resistance. Specifically, we engineered an RPMI8226 MM cell line to express Cas9 and a lentiviral-vector CRISPR library and cultured derived cells in doses of BTZ lethal to parental cells. Sequencing was performed on surviving cells to identify inactivated genes responsible for drug resistance. From two independent whole genome screens, we selected 31 candidate genes and constructed a second CRISPR sgRNA library, specifically targeting each of these 31 genes with four sgRNAs. After secondary screening for BTZ resistance, the top 20 "resistance" genes were selected for individual validation. Of these 20 targets the proteasome regulatory subunit PSMC6 was the only gene validated to reproducibly confer BTZ resistance. We confirmed that inhibition of chymotrypsin-like proteasome activity by BTZ was significantly reduced in cells lacking PSMC6. We individually investigated other members of the PSMC group (PSMC1 to 5) and found that deficiency in each of those subunits also imparts BTZ resistance. We found 36 mutations in 19S proteasome subunits out of 895 patients in the IA10 release of the CoMMapss study (http://ift.tt/2xBOiSL). Our findings demonstrate that the PSMC6 subunit is the most prominent target required for BTZ sensitivity in MM cells and should be examined in drug refractory populations.

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

Genome-wide CRISPR screen for essential cell growth mediators in mutant KRAS colorectal cancers

Targeting mutant KRAS signaling pathways continues to attract attention as a therapeutic strategy for KRAS-driven tumors. In this study, we exploited the power of the CRISPR-Cas9 system to identify genes affecting the tumor xenograft growth of human mutant KRAS colorectal cancers (KRASMUT CRC). Using pooled lentiviral single guide RNA libraries, we conducted a genome-wide loss-of-function genetic screen in an isogenic pair of human CRC cell lines harboring mutant or wild-type KRAS. The screen identified novel and established synthetic enhancers or synthetic lethals for KRASMUT CRC, including targetable metabolic genes. Notably, genetic disruption or pharmacologic inhibition of the metabolic enzymes NAD kinase (NADK) or ketohexokinase (KHK) were growth inhibitory in vivo. Additionally, the chromatin remodeling protein INO80C was identified as a novel tumor suppressor in KRASMUT colorectal and pancreatic tumor xenografts. Our findings define a novel targetable set of therapeutic targets for KRASMUT tumors.

from Cancer via ola Kala on Inoreader http://ift.tt/2xCgG7a
via IFTTT

Genome-wide CRISPR screen for essential cell growth mediators in mutant KRAS colorectal cancers

Targeting mutant KRAS signaling pathways continues to attract attention as a therapeutic strategy for KRAS-driven tumors. In this study, we exploited the power of the CRISPR-Cas9 system to identify genes affecting the tumor xenograft growth of human mutant KRAS colorectal cancers (KRASMUT CRC). Using pooled lentiviral single guide RNA libraries, we conducted a genome-wide loss-of-function genetic screen in an isogenic pair of human CRC cell lines harboring mutant or wild-type KRAS. The screen identified novel and established synthetic enhancers or synthetic lethals for KRASMUT CRC, including targetable metabolic genes. Notably, genetic disruption or pharmacologic inhibition of the metabolic enzymes NAD kinase (NADK) or ketohexokinase (KHK) were growth inhibitory in vivo. Additionally, the chromatin remodeling protein INO80C was identified as a novel tumor suppressor in KRASMUT colorectal and pancreatic tumor xenografts. Our findings define a novel targetable set of therapeutic targets for KRASMUT tumors.

http://ift.tt/2xCgG7a

A phase 1, dose escalation study of oral ASP8273 in patients with non-small cell lung cancers with epidermal growth factor receptor mutations

PURPOSE: Acquired EGFR T790M mutations are the most frequently identified resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs) in patients with EGFR-mutant lung cancers. ASP8273 is a third-generation EGFR TKI with antitumor activity in preclinical models of EGFR-mutant lung cancer that targets mutant EGFR, including EGFR T790M. EXPERIMENTAL DESIGN: In this multi-cohort, phase 1 study (NCT02113813), escalating doses of ASP8273 (25-500mg) were administered once daily to non-small cell lung cancer (NSCLC) patients with disease progression after prior treatment with an EGFR TKI. EGFR T790M was required for all cohorts, except the dose-escalation cohort. Primary endpoints were safety/tolerability; secondary endpoints were determination of the RP2D, pharmacokinetic profile, and preliminary antitumor activity of ASP8273. Evaluation of the use of EGFR mutations in circulating-free DNA (cfDNA) as a biomarker of ASP8273 treatment effects was an exploratory endpoint. RESULTS: A total of 110 patients were treated with ASP8273 across dose-escalation (n=36), response-expansion (n=36), RP2D (300mg; n=19) and food-effect (n=19) cohorts. The most common treatment-emergent adverse events included diarrhea, nausea, fatigue, constipation, vomiting, and hyponatremia. Across all doses, in patients with EGFR T790M, the response rate was 30.7% (n=27/88, 95% CI 19.5-44.5%), and median progression-free survival was 6.8 months (95% CI 5.5-10.1 months). EGFR mutations in cfDNA, both the activating mutation and EGFR T790M, became undetectable in most patients in the setting of clinical response and reemerged upon disease progression. CONCLUSIONS: ASP8273 was well-tolerated and promoted antitumor activity in patients with EGFR-mutant lung cancer with disease progression on prior EGFR TKI therapy.

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

A first-in-human Phase 1 study of the anti-cancer stem cell agent ipafricept (OMP-54F28), a decoy receptor for Wnt ligands, in patients with advanced solid tumors

Purpose: Wnt signaling is implicated in tumor cell de-differentiation and cancer stem cell function. Ipafricept (OMP-54F28) is a first-in-class recombinant fusion protein with the extracellular part of human Frizzled 8 receptor fused to a human IgG1 Fc fragment that binds Wnt ligands. This trial evaluated ipafricept in patients with solid tumors. Experimental Design: A 3+3 design was used; ipafricept was given intravenously every 3 weeks. Objectives were determination of dose-limiting toxicities (DLTs), recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and preliminary efficacy. Results: 26 patients were treated in 7 dose-escalation cohorts (0.5, 1, 2.5, 5, 10, 15 and 20 mg/kg). No further dose escalation was pursued as PK modeling indicated that the target efficacious dose was reached at 10 mg/kg, and fragility fractures occurred at 20 mg/kg. Most common related Grade 1 and 2 adverse events (AEs; ≥20% of patients) were dysgeusia, decreased appetite, fatigue, and muscle spasms. Ipafricept-related Grade 3 TEAEs included hypophosphatemia and weight decrease (1 subject each, 3.8%). Ipafricept half-life was ~4 days, and had low incidence of anti-drug antibody formation (7.69%) with no impact on drug exposure. Six patients had β-C-terminal telopeptide (β-CTX) doubling from baseline, which was reversible. PD modulation of Wnt pathway genes in hair follicles occurred ≥2.5 mg/kg. Two desmoid tumor and a germ cell cancer patient experienced stable disease for >6 months. Conclusions: Ipafricept was well tolerated, with RP2D of 15 mg/kg Q3W. Prolonged SD was noted in desmoid tumor and germ cell cancer patients.

from Cancer via ola Kala on Inoreader http://ift.tt/2xH36ko
via IFTTT

Systemic antitumor immunity by PD-1/PD-L1 inhibition is potentiated by vascular-targeted photodynamic therapy of primary tumors

Purpose: PD-1/PD-L1 pathway inhibition is effective against advanced renal cell carcinoma, although results are variable and may depend on host factors including the tumor microenvironment. Vascular-targeted photodynamic (VTP) therapy with the photosensitizer WST11 induces a defined local immune response, and we sought to determine whether this could potentiate the local and systemic antitumor response to PD-1 pathway inhibition. Experimental Design: Using an orthotopic Renca murine model of renal cell carcinoma that develops lung metastases, we treated primary renal tumors with either VTP alone, PD-1/PD-L1 antagonistic antibodies alone, or a combination of VTP and antibodies, then examined treatment responses including immune infiltration in primary and metastatic sites. Modulation of PD-L1 expression by VTP in human xenograft tumors was also assessed.Results: Treatment of renal tumors with VTP in combination with systemic PD-1/PD-L1 pathway inhibition, but neither treatment alone, resulted in regression of primary tumors, prevented growth of lung metastases and prolonged survival in a preclinical mouse model. Analysis of tumor-infiltrating lymphocytes revealed that treatment effect was associated with increased CD8+:regulatory T cell and CD4+FoxP3-:regulatory T cell ratios in primary renal tumors and increased T cell infiltration in sites of lung metastasis. Furthermore, PD-L1 expression is induced following VTP treatment of human renal cell carcinoma xenografts. Conclusions: Our results demonstrate a role for local immune modulation with VTP in combination with PD-1/PD-L1 pathway inhibition for generation of potent local and systemic antitumor responses. This combined-modality strategy may be an effective therapy in cancers resistant to PD-1/PD-L1 pathway inhibition alone.

from Cancer via ola Kala on Inoreader http://ift.tt/2xHa9tx
via IFTTT

Mutational Analysis of Gene Fusions Predicts Novel MHC Class I-Restricted T cell Epitopes & Immune Signatures in a Subset of Prostate Cancer

Purpose: Gene fusions are frequently found in prostate cancer and may result in the formation of unique chimeric amino acid sequences (CASQs) that span the breakpoint of two fused gene products. This study evaluated the potential for fusion-derived CASQs to be a source of tumor neoepitopes, and determined their relationship to patterns of immune signatures in prostate cancer patients Experimental Design: A computational strategy was used to identify CASQs and their corresponding predicted MHC class I epitopes using RNA-Seq data from The Cancer Genome Atlas of prostate tumors. In vitro peptide-specific T cell expansion was performed to identify CASQ-reactive T cells. A multivariate analysis was used to relate patterns of in silico-predicted tumor-infiltrating immune cells with prostate tumors harboring these mutational events. Results: Eighty-seven percent of tumors contained gene fusions with a mean of 12 per tumor. In total, 41% of fusion-positive tumors were found to encode CASQs. Within these tumors, 87% gave rise to predicted MHC class I-binding epitopes. This observation was more prominent when patients were stratified into low- and intermediate/high-risk categories. One of the identified CASQ from the recurrent TMPRSS2:ERG type VI fusion contained several high-affinity HLA-restricted epitopes. These peptides bound HLA-A*02:01 in vitro and were recognized by CD8+ T cells. Finally, the presence of fusions and CASQs were associated with expression of immune cell infiltration. Conclusions: Mutanome analysis of gene fusion-derived CASQs can give rise to patient-specific predicted neoepitopes. Moreover, these fusions predicted patterns of immune-cell infiltration within a sub-group of prostate cancer patients.

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

The driver mutational landscape of ovarian squamous cell carcinomas arising in mature cystic teratoma

Purpose. We sought to identify the genomic abnormalities in squamous cell carcinomas (SCC) arising in ovarian mature cystic teratoma (MCT), a rare gynaecological malignancy of poor prognosis. Experimental design. We performed copy number, mutational state and zygosity analysis of 151 genes in SCC arising in MCT (n=25) using next-generation sequencing. The presence of high/intermediate risk HPV genotypes was assessed by quantitative PCR. Genomic events were correlated with clinical features and outcome Results. MCT had a low mutation burden with a mean of only 1 mutation per case. Zygosity analyses of MCT indicated four separate patterns, suggesting that MCT can arise from errors at various stages of oogenesis. A total of 244 abnormalities were identified in 79 genes in MCT-associated SCC, and the overall mutational burden was high (mean 10.2 mutations per megabase). No SCC was positive for HPV. The most frequently altered genes in SCC were TP53 (20/25 cases, 80%), PIK3CA (13/25 cases, 52%) and CDKN2A (11/25 cases, 44%). Mutation in TP53 was associated with improved overall survival. In 8/20 cases with TP53 mutations, two or more variants were identified, which were bi-allelic. Conclusions. Ovarian SCC arising in MCT has a high mutational burden with TP53 mutation the most common abnormality. The presence TP53 mutation is a good prognostic factor. SCC arising in MCT share similar mutation profiles to other SCC. Given their rarity, they should be included in basket studies that recruit patients with SCC of other organs.

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

Systemic antitumor immunity by PD-1/PD-L1 inhibition is potentiated by vascular-targeted photodynamic therapy of primary tumors

Purpose: PD-1/PD-L1 pathway inhibition is effective against advanced renal cell carcinoma, although results are variable and may depend on host factors including the tumor microenvironment. Vascular-targeted photodynamic (VTP) therapy with the photosensitizer WST11 induces a defined local immune response, and we sought to determine whether this could potentiate the local and systemic antitumor response to PD-1 pathway inhibition. Experimental Design: Using an orthotopic Renca murine model of renal cell carcinoma that develops lung metastases, we treated primary renal tumors with either VTP alone, PD-1/PD-L1 antagonistic antibodies alone, or a combination of VTP and antibodies, then examined treatment responses including immune infiltration in primary and metastatic sites. Modulation of PD-L1 expression by VTP in human xenograft tumors was also assessed.Results: Treatment of renal tumors with VTP in combination with systemic PD-1/PD-L1 pathway inhibition, but neither treatment alone, resulted in regression of primary tumors, prevented growth of lung metastases and prolonged survival in a preclinical mouse model. Analysis of tumor-infiltrating lymphocytes revealed that treatment effect was associated with increased CD8+:regulatory T cell and CD4+FoxP3-:regulatory T cell ratios in primary renal tumors and increased T cell infiltration in sites of lung metastasis. Furthermore, PD-L1 expression is induced following VTP treatment of human renal cell carcinoma xenografts. Conclusions: Our results demonstrate a role for local immune modulation with VTP in combination with PD-1/PD-L1 pathway inhibition for generation of potent local and systemic antitumor responses. This combined-modality strategy may be an effective therapy in cancers resistant to PD-1/PD-L1 pathway inhibition alone.

http://ift.tt/2xHa9tx

A phase 1, dose escalation study of oral ASP8273 in patients with non-small cell lung cancers with epidermal growth factor receptor mutations

PURPOSE: Acquired EGFR T790M mutations are the most frequently identified resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs) in patients with EGFR-mutant lung cancers. ASP8273 is a third-generation EGFR TKI with antitumor activity in preclinical models of EGFR-mutant lung cancer that targets mutant EGFR, including EGFR T790M. EXPERIMENTAL DESIGN: In this multi-cohort, phase 1 study (NCT02113813), escalating doses of ASP8273 (25-500mg) were administered once daily to non-small cell lung cancer (NSCLC) patients with disease progression after prior treatment with an EGFR TKI. EGFR T790M was required for all cohorts, except the dose-escalation cohort. Primary endpoints were safety/tolerability; secondary endpoints were determination of the RP2D, pharmacokinetic profile, and preliminary antitumor activity of ASP8273. Evaluation of the use of EGFR mutations in circulating-free DNA (cfDNA) as a biomarker of ASP8273 treatment effects was an exploratory endpoint. RESULTS: A total of 110 patients were treated with ASP8273 across dose-escalation (n=36), response-expansion (n=36), RP2D (300mg; n=19) and food-effect (n=19) cohorts. The most common treatment-emergent adverse events included diarrhea, nausea, fatigue, constipation, vomiting, and hyponatremia. Across all doses, in patients with EGFR T790M, the response rate was 30.7% (n=27/88, 95% CI 19.5-44.5%), and median progression-free survival was 6.8 months (95% CI 5.5-10.1 months). EGFR mutations in cfDNA, both the activating mutation and EGFR T790M, became undetectable in most patients in the setting of clinical response and reemerged upon disease progression. CONCLUSIONS: ASP8273 was well-tolerated and promoted antitumor activity in patients with EGFR-mutant lung cancer with disease progression on prior EGFR TKI therapy.

http://ift.tt/2fAostV

The driver mutational landscape of ovarian squamous cell carcinomas arising in mature cystic teratoma

Purpose. We sought to identify the genomic abnormalities in squamous cell carcinomas (SCC) arising in ovarian mature cystic teratoma (MCT), a rare gynaecological malignancy of poor prognosis. Experimental design. We performed copy number, mutational state and zygosity analysis of 151 genes in SCC arising in MCT (n=25) using next-generation sequencing. The presence of high/intermediate risk HPV genotypes was assessed by quantitative PCR. Genomic events were correlated with clinical features and outcome Results. MCT had a low mutation burden with a mean of only 1 mutation per case. Zygosity analyses of MCT indicated four separate patterns, suggesting that MCT can arise from errors at various stages of oogenesis. A total of 244 abnormalities were identified in 79 genes in MCT-associated SCC, and the overall mutational burden was high (mean 10.2 mutations per megabase). No SCC was positive for HPV. The most frequently altered genes in SCC were TP53 (20/25 cases, 80%), PIK3CA (13/25 cases, 52%) and CDKN2A (11/25 cases, 44%). Mutation in TP53 was associated with improved overall survival. In 8/20 cases with TP53 mutations, two or more variants were identified, which were bi-allelic. Conclusions. Ovarian SCC arising in MCT has a high mutational burden with TP53 mutation the most common abnormality. The presence TP53 mutation is a good prognostic factor. SCC arising in MCT share similar mutation profiles to other SCC. Given their rarity, they should be included in basket studies that recruit patients with SCC of other organs.

http://ift.tt/2xGqPRN

Mutational Analysis of Gene Fusions Predicts Novel MHC Class I-Restricted T cell Epitopes & Immune Signatures in a Subset of Prostate Cancer

Purpose: Gene fusions are frequently found in prostate cancer and may result in the formation of unique chimeric amino acid sequences (CASQs) that span the breakpoint of two fused gene products. This study evaluated the potential for fusion-derived CASQs to be a source of tumor neoepitopes, and determined their relationship to patterns of immune signatures in prostate cancer patients Experimental Design: A computational strategy was used to identify CASQs and their corresponding predicted MHC class I epitopes using RNA-Seq data from The Cancer Genome Atlas of prostate tumors. In vitro peptide-specific T cell expansion was performed to identify CASQ-reactive T cells. A multivariate analysis was used to relate patterns of in silico-predicted tumor-infiltrating immune cells with prostate tumors harboring these mutational events. Results: Eighty-seven percent of tumors contained gene fusions with a mean of 12 per tumor. In total, 41% of fusion-positive tumors were found to encode CASQs. Within these tumors, 87% gave rise to predicted MHC class I-binding epitopes. This observation was more prominent when patients were stratified into low- and intermediate/high-risk categories. One of the identified CASQ from the recurrent TMPRSS2:ERG type VI fusion contained several high-affinity HLA-restricted epitopes. These peptides bound HLA-A*02:01 in vitro and were recognized by CD8+ T cells. Finally, the presence of fusions and CASQs were associated with expression of immune cell infiltration. Conclusions: Mutanome analysis of gene fusion-derived CASQs can give rise to patient-specific predicted neoepitopes. Moreover, these fusions predicted patterns of immune-cell infiltration within a sub-group of prostate cancer patients.

http://ift.tt/2fAobHp

A first-in-human Phase 1 study of the anti-cancer stem cell agent ipafricept (OMP-54F28), a decoy receptor for Wnt ligands, in patients with advanced solid tumors

Purpose: Wnt signaling is implicated in tumor cell de-differentiation and cancer stem cell function. Ipafricept (OMP-54F28) is a first-in-class recombinant fusion protein with the extracellular part of human Frizzled 8 receptor fused to a human IgG1 Fc fragment that binds Wnt ligands. This trial evaluated ipafricept in patients with solid tumors. Experimental Design: A 3+3 design was used; ipafricept was given intravenously every 3 weeks. Objectives were determination of dose-limiting toxicities (DLTs), recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and preliminary efficacy. Results: 26 patients were treated in 7 dose-escalation cohorts (0.5, 1, 2.5, 5, 10, 15 and 20 mg/kg). No further dose escalation was pursued as PK modeling indicated that the target efficacious dose was reached at 10 mg/kg, and fragility fractures occurred at 20 mg/kg. Most common related Grade 1 and 2 adverse events (AEs; ≥20% of patients) were dysgeusia, decreased appetite, fatigue, and muscle spasms. Ipafricept-related Grade 3 TEAEs included hypophosphatemia and weight decrease (1 subject each, 3.8%). Ipafricept half-life was ~4 days, and had low incidence of anti-drug antibody formation (7.69%) with no impact on drug exposure. Six patients had β-C-terminal telopeptide (β-CTX) doubling from baseline, which was reversible. PD modulation of Wnt pathway genes in hair follicles occurred ≥2.5 mg/kg. Two desmoid tumor and a germ cell cancer patient experienced stable disease for >6 months. Conclusions: Ipafricept was well tolerated, with RP2D of 15 mg/kg Q3W. Prolonged SD was noted in desmoid tumor and germ cell cancer patients.

http://ift.tt/2xH36ko

Cancer in Peru: The Lancet Oncology

Ben Anderson talks about cancer care and cancer trends in Peru.

http://ift.tt/2fqUSDk

Investigation of magnetic field effects on the dose–response of 3D dosimeters for magnetic resonance – image guided radiation therapy applications

The strong magnetic field of integrated magnetic resonance imaging (MRI) and radiation treatment systems influences secondary electrons resulting in changes in dose deposition in three dimensions. To fill the need for volumetric dose quality assurance, we investigated the effects of strong magnetic fields on 3D dosimeters for MR-image-guided radiation therapy (MR-IGRT) applications.

http://ift.tt/2fQVFOq

Preliminary results of the association of Palbociclib and radiotherapy in metastatic breast cancer patients

There are no published data of the tolerance of combination of Palbociclib and radiotherapy (Palbo-RT). The use of Palbociclib was recently authorized in France for metastatic hormonal receptor (HR) positive HER2 negative breast cancer in association with hormonal therapy in post-menopausal women. A lot of these patients present with symptomatic metastases and they need radiotherapy. The purpose of this paper is to report our very preliminary results of our first patients treated out of research protocols.

http://ift.tt/2xGD4xO

The Effect of Prophylactic Phenylephrine and Ephedrine Infusions on Umbilical Artery Blood pH in Women With Preeclampsia Undergoing Cesarean Delivery With Spinal Anesthesia: A Randomized, Double-Blind Trial.

BACKGROUND: Spinal anesthesia for cesarean delivery is associated with a high incidence of hypotension. Phenylephrine results in higher umbilical artery pH than ephedrine when used to prevent or treat hypotension in healthy women. We hypothesized that phenylephrine compared to ephedrine would result in higher umbilical artery pH in women with preeclampsia undergoing cesarean delivery with spinal anesthesia. METHODS: This study was a randomized double-blind clinical trial. Nonlaboring women with preeclampsia scheduled for cesarean delivery with spinal anesthesia at Prentice Women's Hospital of Northwestern Medicine were randomized to receive prophylactic infusions of phenylephrine or ephedrine titrated to maintain systolic blood pressure >80% of baseline. Spinal anesthesia consisted of hyperbaric 0.75% bupivacaine 12 mg, fentanyl 15 [micro]g, and morphine 150 [micro]g. The primary outcome was umbilical arterial blood pH and the secondary outcome was umbilical artery base excess. RESULTS: One hundred ten women were enrolled in the study and 54 per group were included in the analysis. There were 74 and 72 infants delivered in the ephedrine and phenylephrine groups, respectively. The phenylephrine:ephedrine ratio for umbilical artery pH was 1.002 (95% confidence interval [CI], 0.997-1.007). Mean [standard deviation] umbilical artery pH was not different between the ephedrine 7.20 [0.10] and phenylephrine 7.22 [0.07] groups (mean difference -0.02, 95% CI of the difference -0.06 to 0.07; P = .38). Median (first, third quartiles) umbilical artery base excess was -3.4 mEq/L (-5.7 to -2.0 mEq/L) in the ephedrine group and -2.8 mEq/L (-4.6 to -2.2mEq/L) in the phenylephrine group (difference -0.6 mEq/L, 95% CI of the difference -1.6 to 0.3 mEq/L; P = .10). When adjusted for gestational age and infant gender, umbilical artery pH did not differ between groups. There were also no differences in the umbilical artery pH stratified by magnesium therapy or by the severity of preeclampsia. CONCLUSIONS: We were unable to demonstrate a beneficial effect of phenylephrine on umbilical artery pH compared with ephedrine. Our findings suggest that phenylephrine may not have a clinically important advantage compared with ephedrine with regard to improved neonatal acid-base status when used to prevent spinal anesthesia-induced hypotension in women with preeclampsia undergoing cesarean delivery. (C) 2017 International Anesthesia Research Society

http://ift.tt/2fyn1vO

In Response.

No abstract available

http://ift.tt/2wlnLaR

Understanding the Significance of Aerosolized Vasodilator Use in Pulmonary Hypertension: What Is Numerically, Statistically, and Clinically Meaningful?.

No abstract available

http://ift.tt/2fAeZmi

Mechanisms Supporting Astrocyte-Mediated Neuroprotection.

No abstract available

http://ift.tt/2wkJfEI

The Effect of Zinc Lozenge on Postoperative Sore Throat: A Prospective Randomized, Double-Blinded, Placebo-Controlled Study.

BACKGROUND: Postoperative sore throat (POST) is commonly seen after endotracheal intubation, and oral zinc prevents oral mucositis associated with chemotherapy. This study is designed to evaluate the effects of administration of zinc lozenges on POST. METHODS: Seventy-nine patients undergoing low- or moderate-risk surgery with endotracheal intubation were randomly assigned into 2 groups: Control group received placebo and zinc group received 40-mg zinc lozenges 30 minutes preoperatively. Patients were assessed for incidence and severity (4-point scale, 0-3) of POST at 0, 2, 4, and 24 hours postoperatively. The primary outcome was incidence of POST at 4 hours after surgery. The secondary outcomes were the incidence of POST at 0, 2, and 24 hours and the severity of POST. RESULTS: At 4 hours, there was a significantly lower incidence of POST in the zinc group, 7%, than the control group, 29% (P = .046). The incidence of POST at 0 hour was 0% in zinc group and 24% in control group (P = .004). The highest incidence of POST occurred at the second hour after surgery, with the rate of 10% in the zinc group and 34% in the control group (P = .0495). The incidence of POST at 24 hours was 13% in zinc group and 24% in control group (not significant). The severity of POST was significantly lower in the zinc group for mild (P = .003) and moderate (P = .004) POST. CONCLUSIONS: The administration of a single dose of 40-mg zinc lozenge 30 minutes preoperatively is effective to reduce both incidence of POST in the first 4 hours and severity of mild and moderate POST in the immediate postoperative period. (C) 2017 International Anesthesia Research Society

http://ift.tt/2fAKgFr

[Correspondence] Finding gold in tumour immunotherapy

I read with interest the recent Editorial1 in The Lancet Oncology. The Editorial suggested that immunotherapy is being overhyped and offering false hope to patients with cancer. In the Editorial, advances in immunotherapy were likened to drug developments for EGFR and VEGF inhibitors, which were rolled out with great fanfare but eventually fell short of the initial promise.

http://ift.tt/2xMADdy

[Correspondence] Rituximab and autologous stem-cell transplantation for high-risk diffuse large B-cell lymphoma – Authors' reply

The results from our randomised phase 3 trial1 showed that young patients, affected by high-risk diffuse large B-cell lymphoma (age-adjusted International Prognostic Index score of 2–3), who received abbreviated rituximab-dose-dense chemotherapy plus high dose therapy and autologous stem-cell transplantation compared with patients who received full course rituximab-dose-dense chemotherapy had an improvement in failure-free survival, but not in overall survival.

http://ift.tt/2fzC4oT

[Cancer and Society] A family chronicle of love and death

When Nancy Borowick's father was diagnosed with cancer in 2012, her mother had already been battling the disease for 15 years. Both now had terminal diagnoses, and Borowick, a documentary photographer, set about recording their final months together. The Family Imprint is a handsome book containing these photographs, alongside cards, love notes, old family photos, recipes, diary entries, and interviews with her parents. With it, Borowick creates an indelible family record, one that allowed her to capture and cherish each remaining moment they had together.

http://ift.tt/2xMGLmg

[Clinical Picture] Obstructive sleep apnoea as a presenting manifestation of non-Hodgkin lymphoma in a child

A 14-year-old previously healthy adolescent male patient presented at Rady Children's Hospital (San Diego, CA, USA) in July, 2016, with a history of worsening snoring, recurrent nocturnal awakenings, and daytime somnolence over an 8-month period. Notably, the patient was not overweight or obese; by contrast, he had experienced a weight loss of 7 kg during the same time period. He did not complain of nausea, vomiting, diarrhoea, abdominal pain, dysphagia, or anorexia. Physical examination revealed enlarged tonsils (grade 4, with the left tonsil enlarged more than the right) with deviation of the uvula towards the right.

http://ift.tt/2fzLEYX

[Series] Assessment of cancer control capacity and readiness: the role of the International Atomic Energy Agency

During the past six decades, the International Atomic Energy Agency (IAEA) has helped to address the growing cancer burden, by delivering substantial cancer-related assistance to low-income and middle-income member states. IAEA assistance has primarily been facilitated through sustainable radiotherapy and nuclear medicine programmes to establish safe and effective diagnostic imaging, nuclear medicine, and radiotherapy capacity to safely treat patients with cancer. Planning of a National Cancer Control Programme starts with a needs assessment of all aspects of cancer control in the country to ensure evidence-based strategies are adapted to the country's specific needs.

http://ift.tt/2xMGFuU

[Cancer and Society] Edinburgh Festival Fringe Roundup

Cancer is not one disease but hundreds—not one emperor of maladies but an empire of related conditions sprawling through the human body. Perhaps reflecting that fact, most Edinburgh Fringe Festivals see a glut of shows about cancers of various stripes. Each Fringe exhibits several medically themed shows, dealing with a diversity of conditions from Alzheimer's (2015's It's Dark Outside) to organ donation (Jarlath Regan's impeccably-named Organ Freeman). Nonetheless, shows about other ailments come as single spies; theatrical examinations of cancer come in battalions.

http://ift.tt/2fzLyAz

[Comment] Cancer in Peru: a detailed examination

In 2013, we published a Commission titled, Planning cancer control in Latin America and the Caribbean1 that highlighted the potential harms of an increasing cancer epidemic in a region where infrastructure and funding is ill-equipped to cope with non-communicable diseases. The Commission also detailed specific barriers to cancer control for countries in this region, and suggested possible measures by which these barriers could be overcome. We revisited this area in a second Commission published in 2015, Progress and remaining challenges for cancer control in Latin America and the Caribbean,2 which sought to examine what improvements had been made in the intervening years, what remained to be done, and what new issues had arisen.

http://ift.tt/2xMGyzu

[Series] Resource-stratified implementation of a community-based breast cancer management programme in Peru

Breast cancer incidence and mortality rates continue to rise in Peru, with related deaths projected to increase from 1208 in 2012, to 2054 in 2030. Despite improvements in national cancer control plans, various barriers to positive breast cancer outcomes remain. Multiorganisational stakeholder collaboration is needed for the development of functional, sustainable early diagnosis, treatment and supportive care programmes with the potential to achieve measurable outcomes. In 2011, PATH, the Peruvian Ministry of Health, the National Cancer Institute in Lima, and the Regional Cancer Institute in Trujillo collaborated to establish the Community-based Program for Breast Health, the aim of which was to improve breast health-care delivery in Peru.

http://ift.tt/2fzBJCD

[Cancer and Society] Pharma funding and breast cancer advocacy: the secret war

In Health Advocacy Inc, Sharon Batt chronicles what she dubs the breast cancer advocacy movement's "secret war": the fracturing of the movement over the contentious issue of whether to accept funding from pharmaceutical companies (pharma).

http://ift.tt/2xLcJ23

[Series] The implementation of the Plan Esperanza and response to the imPACT Review

Following the implementation of the National Cancer Prevention and Control Results-based Budget Programme (PpR Cancer–024) in 2011, the Peruvian Government approved the Plan Esperanza—a population-based national cancer control plan—in 2012. Legislation that ensured full government-supported funding for people who were otherwise unable to access or afford care and treatment accompanied the Plan. In 2013, the Ministry of Health requested an integrated mission of the Programme of Action for Cancer Therapy (imPACT) report to strengthen cancer control in Peru.

http://ift.tt/2fzLjWb

[Series] Cancer patterns, trends, and transitions in Peru: a regional perspective

Peru, like several other South American countries, is experiencing remarkable population growth, ageing, and urbanisation, which has given rise to profound changes in its epidemiological profile. Prostate and breast cancer are the most frequent cancers in men and women, respectively, in Lima and Arequipa, the two areas with population-based cancer registries. However, infection-associated cancers (cervix and stomach) are also common, and rank highest in the national cancer mortality profile. Although a foundation of surveillance informs cancer-control initiatives in Peru, improvements in the vital statistics system, and the quality and use of incidence data for the planning and assessment of cancer prevention and control actions, are needed.

http://ift.tt/2xM0D94

[Correspondence] Is it time to convert the frequency of radiotherapy in small-cell lung cancer?

In June, 2017, Corinne Faivre-Finn and colleagues reported the results of the CONVERT trial,1 which adds great value to management guidance for patients with small-cell lung cancer. They reported that once-daily radiotherapy (66 Gy in 33 fractions) did not differ from twice-daily radiotherapy (45 Gy in 30 fractions) in terms of overall survival (HR 1·18, 95% CI 0·95–1·45; p=0·14), local progression-free survival (1·15, 0·93–1·41; p=0·20), metastatic progression-free survival (1·13, 0·92–1·39; p=0·24), or adverse events in patients with small-cell lung cancer.

http://ift.tt/2fzF1pP

[Correspondence] Is it time to convert the frequency of radiotherapy in small-cell lung cancer?

We congratulate Corinne Faivre-Finn and colleagues on their critical phase 3 CONVERT study1 demonstrating non-significant differences in survival outcomes with once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer, with a median overall survival of 25 months in the once-daily group versus 30 months in the twice-daily group (HR 1·18, 95% CI 0·95–1·45; p=0·14), 2-year overall survival of 51% versus 56%, and 5-year overall survival of 31% versus 34%.

http://ift.tt/2xMhUPg

[Correspondence] Rituximab and autologous stem-cell transplantation for high-risk diffuse large B-cell lymphoma

In The Lancet Oncology, Annalisa Chiappella and colleagues1 reported that abbreviated rituximab-dose-dense chemotherapy followed by R-MAD (rituximab plus high-dose cytarabine plus mitoxantrone plus dexamethasone) and high-dose BEAM chemotherapy (carmustine, etoposide, cytarabine, and melphalan) plus autologous stem-cell transplantation reduced the risk of treatment failure compared with full course rituximab-dose-dense chemotherapy (2-year failure-free survival 71% [95% CI 64–77] vs 62% [55–68]; hazard ratio [HR] 0·65, 95% CI 0·47–0·91, stratified log-rank test p=0·012), but resulted in no difference in 5-year overall survival in young patients with diffuse large B-cell lymphoma (78% [95% CI 71–83] vs 77% [71–83]; HR 0·98, 95% CI 0·65–1·48, stratified log-rank test p=0·91).

http://ift.tt/2fztXJ8

[Correspondence] Is it time to convert the frequency of radiotherapy in small-cell lung cancer?

We applaud Corinne Faivre-Finn and colleagues for carrying out an important randomised clinical trial of once-daily versus twice-daily thoracic radiotherapy for patients with limited-stage small-cell lung cancer.1 Management of small-cell lung cancer is undergoing substantial revisions, including the abandonment of prophylactic cranial irradiation2 and incorporation of consolidation thoracic radiotherapy3 in extensive-stage disease.

http://ift.tt/2xMzpyQ

[Correspondence] Is it time to convert the frequency of radiotherapy in small-cell lung cancer? – Authors' reply

We thank Timur Mitin, Chukwuka Eze, and Haiyan Zeng and their colleagues for their interest and comments about the CONVERT trial.1 Mitin and colleagues raise the point that oncologists will consider the result of the trial to be equivalent in terms of whether to provide radiotherapy once-daily or twice-daily. CONVERT was designed to show superiority of once-daily radiotherapy and not powered for equivalence to twice-daily radiotherapy. Furthermore, compliance was better with twice-daily radiotherapy and more patients in this group received the full radiotherapy dose (98% for twice-daily vs 83% for once-daily, p<0·0001) and their planned overall treatment time (63% vs 48%, p=0·0004).

http://ift.tt/2fAtzKg

[Cancer and Society] Growing Up with Cancer

Growing Up with Cancer is an episode from BBC One's Our Lives series broadcasted in June, 2017, and documents the lives and experiences of three ordinary teenagers battling cancer at the Royal Hospital for Children in Glasgow, UK.

http://ift.tt/2xMGiR2

[Correspondence] SRS versus WBRT for resected brain metastases – Authors' reply

We thank Jinbo Yue and Jinming Yu for their interest in our trial, N107C/CEC·3,1 and for their comments. Before implicating worse local control due to lower doses used for large cavities, one must consider that smaller tumours have better outcomes with surgical resection alone than do larger tumours.2 In N107C/CEC·3, surgical bed control was better with whole brain radiotherapy (WBRT) than with stereotactic radiosurgery (SRS) for surgical cavities measuring 3 cm or less (p=0·0005), but the difference in local control was actually not significantly different for surgical cavities larger than 3 cm (p=0·24).

http://ift.tt/2fAtBSo

[Correspondence] SRS versus WBRT for resected brain metastases

We read with interest an article published in The Lancet Oncology by Paul Brown and colleagues.1 In this multicentre, randomised, controlled, phase 3 trial, Brown and colleagues aimed to establish the effect of stereotactic radiosurgery (SRS) on survival and cognitive outcomes compared with whole brain radiotherapy (WBRT) in patients with resected brain metastasis.

http://ift.tt/2xMGhMY

[Editorial] Access to opioids: a balance of harms

Opioid overdose killed 64 070 Americans between 2016–17 to become the leading cause of mortality in the USA for people younger than 50 years. On March 29, 2017, US President Trump gave an executive order to investigate the crisis. The interim report called upon the US Administration to immediately increase capacity for addiction treatment through the removal of the Institutes for Mental Diseases exclusion from Medicaid funding. This recommendation is in stark contrast to this Administration's aim of cutting the government health budget, and Trump has refused to declare the current situation a national emergency, an action that would increase national impetus to act.

http://ift.tt/2fARMjD

Bone marrow sinusoidal endothelium: damage and potential regeneration following cancer radiotherapy or chemotherapy

Abstract

It is very well known that bone marrow (BM) microvasculature may possess a crucial role in the maintenance of homeostasis of BM due to mutual interactions between BM microvascular system and other physiological functions including haematopoiesis and osteogenesis. Chemotherapy and radiotherapy are known as main approaches for cancer treatment and also are known as the main cause of damage to the BM microvascular system. However, despite the importance of BM microvasculature in orchestrating various biological functions, less attention has been drawn to address the underlying mechanisms for the damage and to explore cellular and molecular mechanisms by which the recovery/regeneration of chemotherapy- and/or radiotherapy-induced BM microvascular system damage can occur. Therefore, in this review we firstly discuss the ultra-/structure and biological characteristics of BM microvascular system (sinusoids). Secondly, potential contribution of BM sinusoids is discussed in pathophysiological circumstances (bone remodelling, haematopoiesis, cancer bone metastasis, and haematological cancers). Thirdly, we address previous preclinical and clinical studies regarding chemotherapy- and irradiation-induced BM microvasculature damage. Finally, potential cellular and molecular mechanisms are discussed for the recovery/regeneration of damaged BM microvascular system, including the potential roles of endothelial progenitor cells, haematopoietic stem/progenitor cells, and stimulation of VEGF/VEGFR and Ang-1/Tie-2 signalling pathways.

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

Bone marrow sinusoidal endothelium: damage and potential regeneration following cancer radiotherapy or chemotherapy

Abstract

It is very well known that bone marrow (BM) microvasculature may possess a crucial role in the maintenance of homeostasis of BM due to mutual interactions between BM microvascular system and other physiological functions including haematopoiesis and osteogenesis. Chemotherapy and radiotherapy are known as main approaches for cancer treatment and also are known as the main cause of damage to the BM microvascular system. However, despite the importance of BM microvasculature in orchestrating various biological functions, less attention has been drawn to address the underlying mechanisms for the damage and to explore cellular and molecular mechanisms by which the recovery/regeneration of chemotherapy- and/or radiotherapy-induced BM microvascular system damage can occur. Therefore, in this review we firstly discuss the ultra-/structure and biological characteristics of BM microvascular system (sinusoids). Secondly, potential contribution of BM sinusoids is discussed in pathophysiological circumstances (bone remodelling, haematopoiesis, cancer bone metastasis, and haematological cancers). Thirdly, we address previous preclinical and clinical studies regarding chemotherapy- and irradiation-induced BM microvasculature damage. Finally, potential cellular and molecular mechanisms are discussed for the recovery/regeneration of damaged BM microvascular system, including the potential roles of endothelial progenitor cells, haematopoietic stem/progenitor cells, and stimulation of VEGF/VEGFR and Ang-1/Tie-2 signalling pathways.

http://ift.tt/2xGfYaw

Metastatic Lung Cancer Treated With PD-1/PD-L1 Inhibitors and Radiotherapy

This cohort study evaluates the clinical outcomes in patients with metastatic lung cancer treated with PD-1/PD-L1 inhibitors and thoracic radiotherapy.

from Cancer via ola Kala on Inoreader http://ift.tt/2xCy23C
via IFTTT

Understanding and Communicating Measures of Treatment Effect on Survival: Can We Do Better?

Abstract

Time-to-event end points are the most frequent primary end points in phase III oncology trials, both in the adjuvant and advanced settings. The evaluation of these end points is important to inform clinical practice. However, although different measures can be used to describe the effect of treatment on these end points, we believe that any treatment benefit in a given trial is best reported using various absolute and relative measures. Our goal is to help clinicians understand the strengths and limitations of the traditional and novel measures used to denote the effect of treatment in randomized trials. Although none of these measures can reliably predict the outcome of individual patients, some measures could be added to the commonly used hazard ratio to provide a more patient-oriented assessment of treatment benefit. In particular, the difference of mean survival times quantifies the average survival benefit for a patient receiving a new treatment compared with a patient treated with standard of care, whereas the net benefit quantifies the probability of a patient receiving the new treatment to live longer by at least m months (for any number of months m of interest) than a patient receiving the standard treatment. We encourage statisticians and clinical scientists to include various measures of treatment benefit in the reports of phase III trials, acknowledging that different clinical situations may call for different measures of treatment effect. By using the various available measures, we may better inform ourselves and communicate results to our patients.

http://ift.tt/2wk9bjJ

Nicotinamide Phosphoribosyltransferase (NAMPT) as a Therapeutic Target in BRAF-Mutated Metastatic Melanoma

Abstract

Background

One of the effects of oncogenic signaling is metabolic reprogramming of tumor cells to support anabolic growth, opening the way to therapeutic targeting of metabolic pathways.

Methods

We studied NAD biosynthesis in BRAF inhibitor (BRAFi)–resistant (BiR) melanoma cell lines. Data in cell lines were confirmed by immunohistochemistry in biopsies from 17 patients with metastatic melanoma (MM) before and after the acquisition of resistance to BRAFi. Therapeutic potential of NAD biosynthesis inhibitors was determined by invitro monitoring cell growth and death and in mouse xenograft models. Mice (n = 6–10 mice/group) were treated with nicotinamide phosphoribosyltranferase inhibitor (NAMPTi), BRAFi, or their combination, and tumor growth and survival were analyzed. All statistical tests were two-sided.

Results

BiR cells had higher NAD levels compared with their BRAFi-sensitive counterparts (P < .001 and P = .001 for M14 and A375, respectively) and with normal melanocytes (P < .001), achieved through transcriptional upregulation of the enzyme NAMPT, which became the master regulator of NAD synthesis. Conversely, treatment with BRAFi or MEK inhibitors decreased NAMPT expression and cellular NAD levels. Robust NAMPT upregulation was documented in tissue biopsies from MM patients after development of resistance to BRAFi (P < .001). Treatment of melanoma cells with NAMPTi depleted NAD and ATP, depolarized mitochondrial membrane, and led to reactive oxygen species production, blocking cells in the G2/M phase and inducing apoptosis. Treatment of BiR xenografts with NAMPTi improved mouse survival (median survival of vehicle-treated mice was 52 days vs 100 days for NAMPTi-treated ones in M14/BiR, while in A375/BiR median survival of vehicle-treated mice was 23.5 days vs 43 days for NAMPTi-treated ones, P < .001).

Conclusions

BiR melanoma cells overexpress NAMPT, which acts as a connecting element between BRAF oncogenic signaling and metabolism, becoming an actionable target for this subset of MM patients.

http://ift.tt/2fye8Cr

Met Receptor Tyrosine Kinase and Chemoprevention of Oral Cancer

Abstract

Background

We have previously shown that gene expression profiles of oral leukoplakia (OL) may improve the prediction of oral cancer (OC) risk. To identify new targets for prevention, we performed a systematic survey of transcripts associated with an increased risk of oral cancer and overexpressed in OC vs normal mucosa (NM).

Methods

We used gene expression profiles of 86 patients with OL and available outcomes from a chemoprevention trial of OC and NM. MET expression was evaluated using immunohistochemistry in 120 OL patients, and its association with OC development was tested in multivariable analysis. Sensitivity to pharmacological Met inhibition was tested invitro in premalignant and OC cell lines (n = 33) and invivo using the 4-NQO model of oral chemoprevention (n = 20 mice per group). All statistical tests were two-sided.

Results

The overlap of 693 transcripts associated with an increased risk of OC with 163 transcripts overexpressed in OC compared with NM led to the identification of 23 overlapping transcripts, including MET. MET overexpression in OL was associated with a hazard ratio of 3.84 (95% confidence interval = 1.59 to 9.27, P = .003) of developing OC. Met activation was found in OC and preneoplastic cell lines. Crizotinib activity in preneoplastic and OC cell lines was comparable. ARQ 197 was more active in preneoplastic compared with OC cell lines. In the 4-NQO model, squamous cell carcinoma, dysplasia, and hyperkeratosis were observed in 75.0%, 15.0%, and 10.0% in the control group, and in 25.0%, 70.0%, and 5.0% in the crizotinib group (P < .001).

Conclusion

Together, these data suggest that MET activation may represent an early driver in oral premalignancy and a target for chemoprevention of OC.

http://ift.tt/2fzUWED

Understanding and Communicating Measures of Treatment Effect on Survival: Can We Do Better?

Abstract

Time-to-event end points are the most frequent primary end points in phase III oncology trials, both in the adjuvant and advanced settings. The evaluation of these end points is important to inform clinical practice. However, although different measures can be used to describe the effect of treatment on these end points, we believe that any treatment benefit in a given trial is best reported using various absolute and relative measures. Our goal is to help clinicians understand the strengths and limitations of the traditional and novel measures used to denote the effect of treatment in randomized trials. Although none of these measures can reliably predict the outcome of individual patients, some measures could be added to the commonly used hazard ratio to provide a more patient-oriented assessment of treatment benefit. In particular, the difference of mean survival times quantifies the average survival benefit for a patient receiving a new treatment compared with a patient treated with standard of care, whereas the net benefit quantifies the probability of a patient receiving the new treatment to live longer by at least m months (for any number of months m of interest) than a patient receiving the standard treatment. We encourage statisticians and clinical scientists to include various measures of treatment benefit in the reports of phase III trials, acknowledging that different clinical situations may call for different measures of treatment effect. By using the various available measures, we may better inform ourselves and communicate results to our patients.

from Cancer via ola Kala on Inoreader http://ift.tt/2wk9bjJ
via IFTTT

Nicotinamide Phosphoribosyltransferase (NAMPT) as a Therapeutic Target in BRAF-Mutated Metastatic Melanoma

Abstract

Background

One of the effects of oncogenic signaling is metabolic reprogramming of tumor cells to support anabolic growth, opening the way to therapeutic targeting of metabolic pathways.

Methods

We studied NAD biosynthesis in BRAF inhibitor (BRAFi)–resistant (BiR) melanoma cell lines. Data in cell lines were confirmed by immunohistochemistry in biopsies from 17 patients with metastatic melanoma (MM) before and after the acquisition of resistance to BRAFi. Therapeutic potential of NAD biosynthesis inhibitors was determined by invitro monitoring cell growth and death and in mouse xenograft models. Mice (n = 6–10 mice/group) were treated with nicotinamide phosphoribosyltranferase inhibitor (NAMPTi), BRAFi, or their combination, and tumor growth and survival were analyzed. All statistical tests were two-sided.

Results

BiR cells had higher NAD levels compared with their BRAFi-sensitive counterparts (P < .001 and P = .001 for M14 and A375, respectively) and with normal melanocytes (P < .001), achieved through transcriptional upregulation of the enzyme NAMPT, which became the master regulator of NAD synthesis. Conversely, treatment with BRAFi or MEK inhibitors decreased NAMPT expression and cellular NAD levels. Robust NAMPT upregulation was documented in tissue biopsies from MM patients after development of resistance to BRAFi (P < .001). Treatment of melanoma cells with NAMPTi depleted NAD and ATP, depolarized mitochondrial membrane, and led to reactive oxygen species production, blocking cells in the G2/M phase and inducing apoptosis. Treatment of BiR xenografts with NAMPTi improved mouse survival (median survival of vehicle-treated mice was 52 days vs 100 days for NAMPTi-treated ones in M14/BiR, while in A375/BiR median survival of vehicle-treated mice was 23.5 days vs 43 days for NAMPTi-treated ones, P < .001).

Conclusions

BiR melanoma cells overexpress NAMPT, which acts as a connecting element between BRAF oncogenic signaling and metabolism, becoming an actionable target for this subset of MM patients.

from Cancer via ola Kala on Inoreader http://ift.tt/2fye8Cr
via IFTTT

Analysis of Postoperative Recurrence in Stage I–III Midgut Neuroendocrine Tumors

Abstract

Background

Surgery represents the only curative treatment for stage I–III midgut neuroendocrine tumors (NETs). At present, there are very limited data on the risk of postoperative recurrence. The optimal modality, duration and frequency of surveillance have not been well established. In this work, we investigated the long-term risk of recurrence, peak timing of recurrence, and potential predictors of relapse in patients with stage I–III midgut NETs.

Methods

We retrospectively evaluated 129 patients with stage I–III midgut NETs who were seen at the Moffitt Cancer Center between 2000 and 2010 following an R0/R1 resection. Disease-free survival (DFS) was estimated using the Kaplan-Meier method. Demographic, clinical, and pathological features were assessed as potential predictors of recurrence. All statistical tests were two-sided.

Results

After a median postoperative follow-up of 81 months (range = 1–295 months), recurrence was diagnosed in 40 out of 129 patients (31.0%, 95% confidence interval [CI] = 23.0% to 39.0%). Liver, mesentery, and pelvic lymph nodes were the main sites of relapse. The median DFS was 138 months (95% CI = 117 to 223 months). Resection of 17 or fewer lymph nodes predicted relapse (P = .01) and shorter DFS (P = .04). Among patients who relapsed, the cumulative risks of recurrence at one, five, and 10 years were 15.0% (95% CI = 3.9% to 26.1%), 50.0% (95% CI = 34.5% to 65.5%), and 85.0% (95% CI = 73.9% to 96.0%). No recurrence was observed among patients (n = 6) with stage I tumors, whereas similar rates of relapse were noted in patients with stage II or III NETs (n = 118).

Conclusions

An annual surveillance interval may allow early detection of recurrence. Given the apparent decline in recurrence after eight years from surgery, a decade-long duration of active surveillance may be proposed.

from Cancer via ola Kala on Inoreader http://ift.tt/2wkt7TJ
via IFTTT

Met Receptor Tyrosine Kinase and Chemoprevention of Oral Cancer

Abstract

Background

We have previously shown that gene expression profiles of oral leukoplakia (OL) may improve the prediction of oral cancer (OC) risk. To identify new targets for prevention, we performed a systematic survey of transcripts associated with an increased risk of oral cancer and overexpressed in OC vs normal mucosa (NM).

Methods

We used gene expression profiles of 86 patients with OL and available outcomes from a chemoprevention trial of OC and NM. MET expression was evaluated using immunohistochemistry in 120 OL patients, and its association with OC development was tested in multivariable analysis. Sensitivity to pharmacological Met inhibition was tested invitro in premalignant and OC cell lines (n = 33) and invivo using the 4-NQO model of oral chemoprevention (n = 20 mice per group). All statistical tests were two-sided.

Results

The overlap of 693 transcripts associated with an increased risk of OC with 163 transcripts overexpressed in OC compared with NM led to the identification of 23 overlapping transcripts, including MET. MET overexpression in OL was associated with a hazard ratio of 3.84 (95% confidence interval = 1.59 to 9.27, P = .003) of developing OC. Met activation was found in OC and preneoplastic cell lines. Crizotinib activity in preneoplastic and OC cell lines was comparable. ARQ 197 was more active in preneoplastic compared with OC cell lines. In the 4-NQO model, squamous cell carcinoma, dysplasia, and hyperkeratosis were observed in 75.0%, 15.0%, and 10.0% in the control group, and in 25.0%, 70.0%, and 5.0% in the crizotinib group (P < .001).

Conclusion

Together, these data suggest that MET activation may represent an early driver in oral premalignancy and a target for chemoprevention of OC.

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

“Learning, Education, Awareness, Prevention (L.E.A.P.) Young Adult Cancer”: An Education and Outreach Program

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


http://ift.tt/2xGdR6x

“Learning, Education, Awareness, Prevention (L.E.A.P.) Young Adult Cancer”: An Education and Outreach Program

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


from Cancer via ola Kala on Inoreader http://ift.tt/2xGdR6x
via IFTTT

Highlights from the WIN 2017 Symposium, 26–27 June 2017, Paris, France: ‘Expediting Global Innovation in Precision Cancer Medicine’

Will Davies

http://ift.tt/2wUpSXr

Use of PEG-asparaginase in monomorphic epitheliotropic intestinal T-cell lymphoma, a disease with diagnostic and therapeutic challenges

Cesar Gentille, Qian Qin, Andreia Barbieri, Pingali Sai Ravi and Swaminathan Iyer

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

Highlights from the WIN 2017 Symposium, 26–27 June 2017, Paris, France: ‘Expediting Global Innovation in Precision Cancer Medicine’

Will Davies

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

Whole lung irradiation in stage IV Wilms tumor patients: Thyroid dosimetry and outcomes

Abstract

Purpose

To report the thyroid dosimetry and long-term follow-up of childhood cancer survivors treated with whole lung irradiation (WLI) for Wilms tumor.

Methods

Twenty-eight patients with pulmonary metastases from Wilms tumor who underwent WLI from 2000 TO 2012 at a single institution were reviewed. Radiation dose to the thyroid gland in each case was calculated. Postradiation thyroid function test (TFT) results and management of thyroid function abnormalities were extracted from the medical records.

Results

Median age at treatment was 5 years (range: 1–9 years), and median follow-up time was 74.1 months (7.2–198.4). The male/female ratio was 1:1.8. Complete dosimetry data were available for 22 of the 28 patients receiving WLI. Mean thyroid volume was 3.3 cc (range: 1–6.8). The average mean and median mean dose to the thyroid was 6.7 and 7.1 Gy, respectively (range: 1.3–11.7 Gy). Average max dose to the thyroid was 12.4 Gy (range: 7.8–20.3 Gy). Two patients were found to have a thyroid stimulating hormone (TSH) above the normal range, managed with levothyroxine. Another patient was found to have an isolated elevation of TSH which normalized without treatment. A fourth patient was found to have an enlarged thyroid on examination with no palpable nodules or abnormal TFTs.

Conclusions

Average mean dose to the thyroid gland was 6.7 Gy for this population of stage IV Wilms tumor patients. There was a low rate of thyroid dysfunction, but limited follow-up. Attention to blocking the thyroid gland as much as possible when designing radiation fields can potentially mitigate the risks of long-term thyroid effects.

http://ift.tt/2y9eaZl

DICER1 syndrome: Approach to testing and management at a large pediatric tertiary care center

Abstract

Background

To expand the current knowledge of DICER1 syndrome and to propose criteria for genetic testing based on experience at a pediatric tertiary care center.

Procedure

This study involved a retrospective chart review of the 78 patients (47 probands and 31 family members) seen in the Cancer Genetics Program at The Hospital for Sick Children (SickKids) who were offered genetic testing for DICER1.

Results

Of 47 probands offered genetic testing for DICER1, 46 pursued testing: 11 (23.9%) carried a pathogenic variant and one proband (2.1%) carried a missense variant of uncertain significance with evidence for pathogenicity. Thirty-one family members of variant-positive probands were offered testing: eight of the 25 who agreed to testing carried their familial variant (32.0%). Overall, 20 patients were identified to have a variant in DICER1 (eight males, 12 females). Of these, 13 (65.0%) presented with clinical manifestations associated with the syndrome. The most common lesions were pleuropulmonary blastoma (PPB) (five of 20 patients, 25.0%) and pineoblastoma (three of 20 patients, 15.0%). The average age at which individuals were diagnosed with a primary neoplasm was 5.2 years (range 0.8–20 years, median 3.0). Surveillance at our institution, with a median follow-up time of 23 months, has identified PPB in two asymptomatic individuals. These lesions were identified at early stages, thus potentially reducing treatment-related morbidity and mortality.

Conclusion

This study further delineates the DICER1 syndrome phenotype and demonstrates the feasibility of a DICER1 syndrome surveillance protocol for the early detection of tumors.

http://ift.tt/2y7S21g

Whole lung irradiation in stage IV Wilms tumor patients: Thyroid dosimetry and outcomes

Abstract

Purpose

To report the thyroid dosimetry and long-term follow-up of childhood cancer survivors treated with whole lung irradiation (WLI) for Wilms tumor.

Methods

Twenty-eight patients with pulmonary metastases from Wilms tumor who underwent WLI from 2000 TO 2012 at a single institution were reviewed. Radiation dose to the thyroid gland in each case was calculated. Postradiation thyroid function test (TFT) results and management of thyroid function abnormalities were extracted from the medical records.

Results

Median age at treatment was 5 years (range: 1–9 years), and median follow-up time was 74.1 months (7.2–198.4). The male/female ratio was 1:1.8. Complete dosimetry data were available for 22 of the 28 patients receiving WLI. Mean thyroid volume was 3.3 cc (range: 1–6.8). The average mean and median mean dose to the thyroid was 6.7 and 7.1 Gy, respectively (range: 1.3–11.7 Gy). Average max dose to the thyroid was 12.4 Gy (range: 7.8–20.3 Gy). Two patients were found to have a thyroid stimulating hormone (TSH) above the normal range, managed with levothyroxine. Another patient was found to have an isolated elevation of TSH which normalized without treatment. A fourth patient was found to have an enlarged thyroid on examination with no palpable nodules or abnormal TFTs.

Conclusions

Average mean dose to the thyroid gland was 6.7 Gy for this population of stage IV Wilms tumor patients. There was a low rate of thyroid dysfunction, but limited follow-up. Attention to blocking the thyroid gland as much as possible when designing radiation fields can potentially mitigate the risks of long-term thyroid effects.

from Cancer via ola Kala on Inoreader http://ift.tt/2y9eaZl
via IFTTT

Wrangling with P-values

from Cancer via ola Kala on Inoreader http://ift.tt/2k5Jli3
via IFTTT

DICER1 syndrome: Approach to testing and management at a large pediatric tertiary care center

Abstract

Background

To expand the current knowledge of DICER1 syndrome and to propose criteria for genetic testing based on experience at a pediatric tertiary care center.

Procedure

This study involved a retrospective chart review of the 78 patients (47 probands and 31 family members) seen in the Cancer Genetics Program at The Hospital for Sick Children (SickKids) who were offered genetic testing for DICER1.

Results

Of 47 probands offered genetic testing for DICER1, 46 pursued testing: 11 (23.9%) carried a pathogenic variant and one proband (2.1%) carried a missense variant of uncertain significance with evidence for pathogenicity. Thirty-one family members of variant-positive probands were offered testing: eight of the 25 who agreed to testing carried their familial variant (32.0%). Overall, 20 patients were identified to have a variant in DICER1 (eight males, 12 females). Of these, 13 (65.0%) presented with clinical manifestations associated with the syndrome. The most common lesions were pleuropulmonary blastoma (PPB) (five of 20 patients, 25.0%) and pineoblastoma (three of 20 patients, 15.0%). The average age at which individuals were diagnosed with a primary neoplasm was 5.2 years (range 0.8–20 years, median 3.0). Surveillance at our institution, with a median follow-up time of 23 months, has identified PPB in two asymptomatic individuals. These lesions were identified at early stages, thus potentially reducing treatment-related morbidity and mortality.

Conclusion

This study further delineates the DICER1 syndrome phenotype and demonstrates the feasibility of a DICER1 syndrome surveillance protocol for the early detection of tumors.

from Cancer via ola Kala on Inoreader http://ift.tt/2y7S21g
via IFTTT