Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Τετάρτη 19 Ιουλίου 2017
Prévention médicale et traitement des complications pulmonaires secondaires à la radiothérapie
Source:Cancer/Radiothérapie
Author(s): A. Vallard, C. Rancoule, H. Le Floch, J.-B. Guy, S. Espenel, C. Le Péchoux, É. Deutsch, N. Magné, C. Chargari
http://ift.tt/2tJ6Z3a
Role of anesthesia in endovascular stroke therapy.
Purpose of review: Recent randomized clinical trials have demonstrated strong efficacy of endovascular therapy (EVT) for acute ischemic stroke (AIS) from large vessel occlusions; in the USA alone, tens of thousands of patients annually may benefit. The impact of the type of anesthesia used during mechanical thrombectomy on patient outcomes remains controversial. This review discusses the current literature on the effects of anesthesia type on patient outcome following endovascular stroke therapy. Recent findings: EVT is the standard of treatment for intracranial large vessel occlusions. Recent studies show that general anesthesia is associated with negative clinical outcome in AIS patients undergoing EVT. Two of the possible mechanisms of this finding are systolic hypotension and hypocapnia. However, the only published randomized controlled studies to date, sedation vs. intubation for endovascular stroke treatment and anesthesia during stroke showed no difference in short-term clinical outcome between EVT patients treated with general anesthesia and conscious sedation and improved longer-term outcome in the general anesthesia group. Summary: Retrospective reports, and the 2015 American Heart Association/American Stroke Association Guideline (focused update of the 2013 guidelines for the early management of patients with AIS regarding endovascular treatment) based on these reports, are in favor of sedation (conscious sedation) over general anesthesia for endovascular stroke thrombectomy. However, the two randomized controlled prospective studies published provide inconclusive evidence as to the best anesthetic practice for endovascular stroke therapy. More randomized clinical trials are needed to optimize anesthetic patient care in AIS. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.
http://ift.tt/2vlisYT
http://ift.tt/2vlisYT
Incidence Trends of Cervical Cancer in Adolescents and Young Adults: Brazilian Population Based Data
Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.
http://online.liebertpub.com/doi/abs/10.1089/jayao.2017.0048?ai=2102&mi=6mjyqr&af=R
Functioning metastatic paraganglioma of the urinary bladder in a 10-year-old child
Paragangliomas of the urinary bladder are very rare tumours representing less than 1% of bladder tumours. Preoperative diagnosis is essential to avoid perioperative complications related to catecholamine release. A high index of suspicion should be maintained when the classical symptoms of voiding-related paroxysms of headache, palpitation and dizziness are present. We present a rare case of malignant paraganglioma of the urinary bladder in a 10-year-old boy. The patient had the classic presentation. We review the radiological diagnostic tools and findings of this rare entity.
http://casereports.bmj.com/cgi/content/short/2017/jul19_2/bcr-2017-220533?rss=1
Abundant dystrophic calcifications mimicking aortic valve abscess in a patient undergoing elective aortic valve replacement
Dystrophic calcifications of the aortic valve may cause symptomatic aortic stenosis and account for a significant portion of patients who undergo elective valve replacement. Calcifications appearing grossly as a cloudy fluid surrounding the aortic valve leaflets are an uncommon finding. Normally, calcified aortic valves are characterised by large, nodular masses within the aortic cusps. We report a case of dystrophic calcifications on a stenotic aortic valve encountered intraoperatively, which was suggestive of infective endocarditis and abscess formation. Aortic valve leaflets and necrotic-appearing thymic lymph node tissue were submitted for histology and special stains. Cultures were negative and histology did not show evidence of infection. Tissue histology demonstrated extensive dystrophic calcifications, which were polarised to reveal abundant calcium oxalate crystals. The benign nature of this unique pathological finding ruled out any suspicion of infection, avoiding a prolonged course of intravenous antibiotics in this patient.
http://casereports.bmj.com/cgi/content/short/2017/jul19_2/bcr-2017-220368?rss=1
Very early great saphenous vein graft aneurysm treated by percutaneous coronary intervention under ChromaFlo imaging guidance
A 73-year-old man, who had undergone coronary artery bypass grafting (CABG) 10 days prior, presented with a great saphenous vein graft aneurysm (SVGA). CT revealed the increasing size of the aneurysm. Since the SVGA occurred immediately after CABG and there were no other complications, the aneurysm was treated percutaneously. While intravascular ultrasonography (IVUS) and optical coherence tomography failed to detect the entry point, an IVUS catheter with the addition of ChromaFlo imaging clearly revealed the entry point, size and length of the SVGA. To prevent migration and edge restenosis associated with covered stents, the covered stent (3.0x19 mm) was superimposed on a drug-eluting stent (3.0x28 mm) that covered the entry site. A follow-up study demonstrated the absence of flow into the aneurysm.
http://casereports.bmj.com/cgi/content/short/2017/jul19_2/bcr-2017-220443?rss=1
Arthroscopic excision of an intra-articular osteoid osteoma in the elbow joint
An osteoid osteoma is a rare, small, benign and painful tumour occurring in the extra-articular portion of long bones seen most commonly in the lower extremities. This is a case report of a 23-year-old female patient who underwent arthroscopic resection of an intra-articular osteoid osteoma. The nidus was completely removed by arthroscopic excision. The diagnosis was confirmed by postoperative histopathological analysis. In the case presented we have shown that intra-articular arthroscopy can be successful in the surgical management of benign bony lesions involving the elbow joint. We also present a review of the literature which reports on similar cases or intra-articular disease, preferred methods of surgical management and limitations in histopathological specimen acquisition for diagnosis.
http://casereports.bmj.com/cgi/content/short/2017/jul19_2/bcr-2017-220868?rss=1
Long-term peritoneal port-catheter in a patient with cardiac ascites
A peritoneal port-catheter was inserted in a 70-year-old man because of repeated paracentesis due to cardiac ascites. Instead of frequent hospital admissions, the patient could drain his ascites at home, which dramatically improved his quality of life and enabled him to perform his daily activities.
http://casereports.bmj.com/cgi/content/short/2017/jul19_2/bcr-2017-219258?rss=1
Atypical responses in patients with advanced melanoma, lung cancer, renal-cell carcinoma and other solid tumors treated with anti-PD-1 drugs: A Systematic Review
Source:Cancer Treatment Reviews
Author(s): Paola Queirolo, Francesco Spagnolo
Anti-programmed death receptor 1 (PD-1) drugs nivolumab and pembrolizumab were recently approved for the treatment of advanced melanoma and other solid tumors. Atypical patterns of response (i.e. tumor shrinkage or stabilization after initial progression) were observed in about 10% of metastatic melanoma patients treated with anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) drug ipilimumab and were associated with improved survival; however, the rate of atypical response patterns to anti-PD-1 therapy is not clear. An electronic search was performed to identify clinical trials evaluating response to anti-PD-1 therapy with nivolumab and pembrolizumab in patients with advanced solid tumors.Thirty-eight studies were included in our analysis for a total of 7069 patients with advanced cancer treated with anti-PD-1 therapy. Responses were evaluated by unconventional response criteria in 19 trials and were observed for all cancer types but tumors with mismatch-repair deficiency and head and neck squamous cell carcinoma. Overall, 151 atypical responses were observed in 2400 patients (6%) evaluated by unconventional response criteria.The results of our systematic review highlight the clinical relevance of unconventional responses to anti-PD-1 therapy and support further investigation into the development of tools that may assist evaluation of the antitumor activity of immunotherapy.
http://rss.sciencedirect.com/action/redirectFile?&zone=main¤tActivity=feed&usageType=outward&url=http%3A%2F%2Fwww.sciencedirect.com%2Fscience%3F_ob%3DGatewayURL%26_origin%3DIRSSSEARCH%26_method%3DcitationSearch%26_piikey%3DS030573721730107X%26_version%3D1%26md5%3Df8a05d9001211f499623971c50e84160
The novel autophagy inhibitor elaiophylin exerts antitumor activity against multiple myeloma with mutant TP53 in part through endoplasmic reticulum stress-induced apoptosis.
| Related Articles |
The novel autophagy inhibitor elaiophylin exerts antitumor activity against multiple myeloma with mutant TP53 in part through endoplasmic reticulum stress-induced apoptosis.
Cancer Biol Ther. 2017 Jul 18;:0
Authors: Gaoxiang W, Pan Z, Xing C, Zhao L, Jiaqi T, Yang Y, Fang Y, Zhou J
Abstract
Elaiophylin is a natural compound and a novel and potent inhibitor of late stage autophagy with outstanding antitumor activity in human ovarian cancer cells. However, the possible biological effects and functional linkage between elaiophylin and multiple myeloma (MM) have not been explored. This study aimed to assess the effect of elaiophylin on MM cells with mutant TP53 and the possible molecular mechanism. The results suggested that elaiophylin exerted anti-myeloma activity by inducing apoptosis and proliferation arrest. As expected, elaiophylin blocked autophagy flux in MM cells. Subsequently, persistent activation of endoplasmic reticulum (ER) stress was induced. Moreover, the apoptotic effect was to some extent attenuated by the ER stress inhibitor tauroursodeoxycholic acid (TUDCA). Further studies indicated that elaiophylin effectively suppressed MM cell growth without obvious side effects in zebrafish embryo and mouse xenograft models. Taken together, our data are the first to demonstrate that exposure of human MM cells with mutant TP53 to elaiophylin blocked autophagy flux and thus induced cell death, which partially involved ER stress-associated apoptosis. Targeted disruption of the cellular protein handling system by elaiophylin is therefore a promising therapeutic strategy for overcoming incurable MM, even when TP53 mutations are present.
PMID: 28718729 [PubMed - as supplied by publisher]
from Cancer via ola Kala on Inoreader http://ift.tt/2vDWGPo
via IFTTT
Enhanced procoagulant activity of platelets after chemotherapy in non-small cell lung cancer.
| Related Articles |
Enhanced procoagulant activity of platelets after chemotherapy in non-small cell lung cancer.
Cancer Biol Ther. 2017 Jul 18;:0
Authors: Ma R, Bi Y, Kou J, Zhou J, Shi J
Abstract
The procoagulant status of patients with non-small cell lung cancer (NSCLC) after chemotherapy is poorly characterized and the role of platelets in hypercoagulative state of NSCLC is unknown. The aim of this study was to evaluate the procoagulant activity (PCA) of platelets in NSCLC before and after chemotherapy. The subjects were 52 patients newly diagnosed with NSCLC. The patients had decreased clotting time compared with healthy subjects, and the thrombin-antithrombin complex increased 2.5 fold after chemotherapy. Platelets in the patients after chemotherapy had enhanced phosphatidylserine (PS) exposure, and shortened coagulation time as well as increased thrombin and fibrin formation of platelets compared with those before chemotherapy. Platelet-derived microparticles increased 2 fold at day 1 and peaked at day 2 post-chemotherapy. Treatment of cisplatin in vitro also resulted in upregulated intrinsic FXa and thrombin formation on platelets with a dose-dependent manner. Platelets treated with aspirin significantly decreased PCA. However, lactadherin blocked PS and inhibited the PCA approximately by 70%. Seven days after chemotherapy, PCA of platelets restored to the baseline as that before chemotherapy, indicating that within a week of chemotherapy patient platelets are highly procoagulant and effective intervention should be taken in case of thrombosis. Our results suggested that platelets after chemotherapy had elevated PCA and may contribute to the hypercoagulative state of NSCLC. Prophylactic anti-coagulant combined with anti-platelet therapy may play an inhibitory role in thrombotic complications in NSCLC.
PMID: 28718695 [PubMed - as supplied by publisher]
from Cancer via ola Kala on Inoreader http://ift.tt/2vDNx9l
via IFTTT
Identification of new tumor suppressor genes in triple-negative breast cancer
Although genomic sequencing has provided a better understating of the genetic landmarks in triple-negative breast cancer (TNBC), functional validation of candidate cancer genes (CCG) remains unsolved. In this study, we used a transposon mutagenesis strategy based on a two-step Sleeping Beauty (SB) forward genetic screen to identify and validate new tumor suppressors (TS) in this disease. We generated 120 siRNAs targeting 40 SB-identified candidate breast cancer TS genes and used them to downregulate expression of these genes in four human TNBC cell lines. Among CCG whose SB-mediated genetic mutation resulted in increased cellular proliferation in all cell lines tested, the genes ADNP, AP2B1, TOMM70A and ZNF326 showed tumor suppressor (TS) activity in tumor xenograft studies. Subsequent studies showed that ZNF326 regulated expression of multiple EMT and cancer stem cell (CSC) pathway genes. It also modulated expression of TS genes involved in the regulation of migration and cellular invasion and was a direct transcriptional activator of genes that regulate CSC self-renewal. ZNF326 expression associated with TNBC patient survival, with ZNF326 protein levels showing a marked reduction in TNBC. Our validation of several new tumor suppressor genes in TNBC demonstrate the utility of two-step forward genetic screens in mice, and offer an invaluable tool to identify novel candidate therapeutic pathways and targets.
from Cancer via ola Kala on Inoreader http://ift.tt/2u9PQkX
via IFTTT
Our panel of experts highlights the most important research articles across the spectrum of topics relevant to the field of CNS oncology
CNS Oncology, Ahead of Print.
from Cancer via ola Kala on Inoreader http://ift.tt/2u9MK0v
via IFTTT
CNS Anticancer Drug Discovery and Development: 2016 conference insights
CNS Oncology, Ahead of Print.
from Cancer via ola Kala on Inoreader http://ift.tt/2trPYPV
via IFTTT
The role of surgery in low-grade gliomas: do timing and extent of resection matter?
CNS Oncology, Ahead of Print.
from Cancer via ola Kala on Inoreader http://ift.tt/2u9PH0W
via IFTTT
Savolitinib Heads for Phase III Trial in PRCC [News in Brief]
MET inhibitor shows promise treating papillary renal cell carcinoma in patients with abnormalities in MET signaling pathway.
from Cancer via ola Kala on Inoreader http://ift.tt/2tIsocY
via IFTTT
Phase I dose escalation study of NMS-1286937, an orally available Polo-Like Kinase 1 inhibitor, in patients with advanced or metastatic solid tumors
Summary
Background Pharmacological inhibition of polo-like kinase 1 (PLK1) represents a new approach for the treatment of solid tumors. This study was aimed at determining the first cycle dose-limiting toxicities (DLTs) and related maximum tolerated dose (MTD) of NMS-1286937, a selective ATP-competitive PLK1-specific inhibitor. Secondary objectives included evaluation of its safety and pharmacokinetic (PK) profile in plasma, its antitumor activity, and its ability to modulate intracellular targets in biopsied tissue. Methods This was a Phase I, open-label, dose-escalation trial in patients with advanced/metastatic solid tumors. A treatment cycle comprised 5 days of oral administration followed by 16 days of rest, for a total of 21 days (3-week cycle). Results Nineteen of 21 enrolled patients with confirmed metastatic disease received study medication. No DLTs occurred at the first 3 dose levels (6, 12, and 24 mg/m2/day). At the subsequent dose level (48 mg/m2/day), 2 of 3 patients developed DLTs. An intermediate level of 36 mg/m2/day was therefore investigated. Four patients were treated and two DLTs were observed. After further cohort expansion, the MTD and recommended phase II dose (RP2D) were determined to be 24 mg/m2/day. Disease stabilization, observed in several patients, was the best treatment response observed. Hematological toxicity (mostly thrombocytopenia and neutropenia) was the major DLT. Systemic exposure to NMS-1286937 increased with dose and was comparable between two cycles of treatment following oral administration of the drug. Conclusions This study successfully identified the MTD and DLTs for NMS-1286937 and characterized its safety profile.
from Cancer via ola Kala on Inoreader http://ift.tt/2tIATEI
via IFTTT
The novel autophagy inhibitor elaiophylin exerts antitumor activity against multiple myeloma with mutant TP53 in part through endoplasmic reticulum stress-induced apoptosis.
| Related Articles |
The novel autophagy inhibitor elaiophylin exerts antitumor activity against multiple myeloma with mutant TP53 in part through endoplasmic reticulum stress-induced apoptosis.
Cancer Biol Ther. 2017 Jul 18;:0
Authors: Gaoxiang W, Pan Z, Xing C, Zhao L, Jiaqi T, Yang Y, Fang Y, Zhou J
Abstract
Elaiophylin is a natural compound and a novel and potent inhibitor of late stage autophagy with outstanding antitumor activity in human ovarian cancer cells. However, the possible biological effects and functional linkage between elaiophylin and multiple myeloma (MM) have not been explored. This study aimed to assess the effect of elaiophylin on MM cells with mutant TP53 and the possible molecular mechanism. The results suggested that elaiophylin exerted anti-myeloma activity by inducing apoptosis and proliferation arrest. As expected, elaiophylin blocked autophagy flux in MM cells. Subsequently, persistent activation of endoplasmic reticulum (ER) stress was induced. Moreover, the apoptotic effect was to some extent attenuated by the ER stress inhibitor tauroursodeoxycholic acid (TUDCA). Further studies indicated that elaiophylin effectively suppressed MM cell growth without obvious side effects in zebrafish embryo and mouse xenograft models. Taken together, our data are the first to demonstrate that exposure of human MM cells with mutant TP53 to elaiophylin blocked autophagy flux and thus induced cell death, which partially involved ER stress-associated apoptosis. Targeted disruption of the cellular protein handling system by elaiophylin is therefore a promising therapeutic strategy for overcoming incurable MM, even when TP53 mutations are present.
PMID: 28718729 [PubMed - as supplied by publisher]
from Cancer via ola Kala on Inoreader http://ift.tt/2vDWGPo
via IFTTT
Enhanced procoagulant activity of platelets after chemotherapy in non-small cell lung cancer.
| Related Articles |
Enhanced procoagulant activity of platelets after chemotherapy in non-small cell lung cancer.
Cancer Biol Ther. 2017 Jul 18;:0
Authors: Ma R, Bi Y, Kou J, Zhou J, Shi J
Abstract
The procoagulant status of patients with non-small cell lung cancer (NSCLC) after chemotherapy is poorly characterized and the role of platelets in hypercoagulative state of NSCLC is unknown. The aim of this study was to evaluate the procoagulant activity (PCA) of platelets in NSCLC before and after chemotherapy. The subjects were 52 patients newly diagnosed with NSCLC. The patients had decreased clotting time compared with healthy subjects, and the thrombin-antithrombin complex increased 2.5 fold after chemotherapy. Platelets in the patients after chemotherapy had enhanced phosphatidylserine (PS) exposure, and shortened coagulation time as well as increased thrombin and fibrin formation of platelets compared with those before chemotherapy. Platelet-derived microparticles increased 2 fold at day 1 and peaked at day 2 post-chemotherapy. Treatment of cisplatin in vitro also resulted in upregulated intrinsic FXa and thrombin formation on platelets with a dose-dependent manner. Platelets treated with aspirin significantly decreased PCA. However, lactadherin blocked PS and inhibited the PCA approximately by 70%. Seven days after chemotherapy, PCA of platelets restored to the baseline as that before chemotherapy, indicating that within a week of chemotherapy patient platelets are highly procoagulant and effective intervention should be taken in case of thrombosis. Our results suggested that platelets after chemotherapy had elevated PCA and may contribute to the hypercoagulative state of NSCLC. Prophylactic anti-coagulant combined with anti-platelet therapy may play an inhibitory role in thrombotic complications in NSCLC.
PMID: 28718695 [PubMed - as supplied by publisher]
from Cancer via ola Kala on Inoreader http://ift.tt/2vDNx9l
via IFTTT
The novel autophagy inhibitor elaiophylin exerts antitumor activity against multiple myeloma with mutant TP53 in part through endoplasmic reticulum stress-induced apoptosis.
| Related Articles |
The novel autophagy inhibitor elaiophylin exerts antitumor activity against multiple myeloma with mutant TP53 in part through endoplasmic reticulum stress-induced apoptosis.
Cancer Biol Ther. 2017 Jul 18;:0
Authors: Gaoxiang W, Pan Z, Xing C, Zhao L, Jiaqi T, Yang Y, Fang Y, Zhou J
Abstract
Elaiophylin is a natural compound and a novel and potent inhibitor of late stage autophagy with outstanding antitumor activity in human ovarian cancer cells. However, the possible biological effects and functional linkage between elaiophylin and multiple myeloma (MM) have not been explored. This study aimed to assess the effect of elaiophylin on MM cells with mutant TP53 and the possible molecular mechanism. The results suggested that elaiophylin exerted anti-myeloma activity by inducing apoptosis and proliferation arrest. As expected, elaiophylin blocked autophagy flux in MM cells. Subsequently, persistent activation of endoplasmic reticulum (ER) stress was induced. Moreover, the apoptotic effect was to some extent attenuated by the ER stress inhibitor tauroursodeoxycholic acid (TUDCA). Further studies indicated that elaiophylin effectively suppressed MM cell growth without obvious side effects in zebrafish embryo and mouse xenograft models. Taken together, our data are the first to demonstrate that exposure of human MM cells with mutant TP53 to elaiophylin blocked autophagy flux and thus induced cell death, which partially involved ER stress-associated apoptosis. Targeted disruption of the cellular protein handling system by elaiophylin is therefore a promising therapeutic strategy for overcoming incurable MM, even when TP53 mutations are present.
PMID: 28718729 [PubMed - as supplied by publisher]
from Cancer via ola Kala on Inoreader http://ift.tt/2vDWGPo
via IFTTT
Enhanced procoagulant activity of platelets after chemotherapy in non-small cell lung cancer.
| Related Articles |
Enhanced procoagulant activity of platelets after chemotherapy in non-small cell lung cancer.
Cancer Biol Ther. 2017 Jul 18;:0
Authors: Ma R, Bi Y, Kou J, Zhou J, Shi J
Abstract
The procoagulant status of patients with non-small cell lung cancer (NSCLC) after chemotherapy is poorly characterized and the role of platelets in hypercoagulative state of NSCLC is unknown. The aim of this study was to evaluate the procoagulant activity (PCA) of platelets in NSCLC before and after chemotherapy. The subjects were 52 patients newly diagnosed with NSCLC. The patients had decreased clotting time compared with healthy subjects, and the thrombin-antithrombin complex increased 2.5 fold after chemotherapy. Platelets in the patients after chemotherapy had enhanced phosphatidylserine (PS) exposure, and shortened coagulation time as well as increased thrombin and fibrin formation of platelets compared with those before chemotherapy. Platelet-derived microparticles increased 2 fold at day 1 and peaked at day 2 post-chemotherapy. Treatment of cisplatin in vitro also resulted in upregulated intrinsic FXa and thrombin formation on platelets with a dose-dependent manner. Platelets treated with aspirin significantly decreased PCA. However, lactadherin blocked PS and inhibited the PCA approximately by 70%. Seven days after chemotherapy, PCA of platelets restored to the baseline as that before chemotherapy, indicating that within a week of chemotherapy patient platelets are highly procoagulant and effective intervention should be taken in case of thrombosis. Our results suggested that platelets after chemotherapy had elevated PCA and may contribute to the hypercoagulative state of NSCLC. Prophylactic anti-coagulant combined with anti-platelet therapy may play an inhibitory role in thrombotic complications in NSCLC.
PMID: 28718695 [PubMed - as supplied by publisher]
from Cancer via ola Kala on Inoreader http://ift.tt/2vDNx9l
via IFTTT
Ellagic Acid Enhances Apoptotic Sensitivity of Breast Cancer Cells to γ-Radiation.
| Related Articles |
Ellagic Acid Enhances Apoptotic Sensitivity of Breast Cancer Cells to γ-Radiation.
Nutr Cancer. 2017 Jul 18;:1-7
Authors: Ahire V, Kumar A, Mishra KP, Kulkarni G
Abstract
Herbal polyphenols have gained increased significance because of the promises they hold in the prevention and treatment of cancer. There exists an enormous opportunity for the screening and valuation of natural dietary compounds in the development of an effective chemopreventive drug and radiosensitizer that may be of practical use for patients undergoing cancer therapy. This study describes the effect of the flavonoid ellagic acid (EA) on gamma-irradiated human breast cancer MCF-7 cells in vitro when administered alone or in combination with radiation. It was interesting to find the radioprotective effect of EA on NIH3T3, which is a normal cell line. Irradiation of breast tumor cells in the presence of EA (10 μM) to doses of 2 and 4-Gy gamma radiation produced a marked synergistic tumor cytotoxicity while it was found to aid recovery from the radiation damage to NIH3T3 cells. When cells were given a combined treatment of EA and radiation, the cell death increased to 21.7% and 20.7% in the 2 and 4-Gy-treated cells respectively, significantly (P < 0.05) reducing the capacity of MCF-7 cells to form colonies. Even at 24 h, 38 foci/cell were observed in samples that were given the combined treatment, suggesting the cells' inability in repairing the damage. Also, increased apoptosis in EA+ 2Gy (50%) and EA+ 4 Gy (62%)-treated cells was observed in the the sub-G1 phase of the cell cycle. A 6.2-fold decrease in the mitochondrial membrane potential was observed in the combined treatment of EA and IR that facilitated the upregulation of pro-apopttotic Bax and downregulation of Bcl-2, pushing the MCF-7 cells to undergo an apoptotic cell death. It is suggested that EA may be a potential drug adjuvant for improving cancer radiotherapy by increasing tumor toxicity and reducing the normal cell damage caused by irradiation.
PMID: 28718725 [PubMed - as supplied by publisher]
from Cancer via ola Kala on Inoreader http://ift.tt/2uKMkRx
via IFTTT
Black Raspberries and Their Anthocyanin and Fiber Fractions Alter the Composition and Diversity of Gut Microbiota in F-344 Rats.
| Related Articles |
Black Raspberries and Their Anthocyanin and Fiber Fractions Alter the Composition and Diversity of Gut Microbiota in F-344 Rats.
Nutr Cancer. 2017 Jul 18;:1-9
Authors: Pan P, Lam V, Salzman N, Huang YW, Yu J, Zhang J, Wang LS
Abstract
Natural compounds can alter the diversity and composition of the gut microbiome, potentially benefiting our health. We previously demonstrated chemopreventive effects of black raspberries (BRBs) in colorectal cancer, which is associated with gut dysbiosis. To investigate the effects of whole BRBs and their fractions on gut microbiota, we fed F-344 rats a control diet, 5% BRBs, the BRB anthocyanin fraction, or the BRB residue fraction for 6 weeks. Feces were collected at baseline and at weeks 3 and 6, and bacterial sequence counts were analyzed. We observed distinct patterns of microbiota from different diet groups. Beta diversity analysis suggested that all diet groups exerted time-dependent changes in the bacterial diversity. Hierarchical clustering analysis revealed that post-diet fecal microbiota was segregated from baseline fecal microbiota within each diet. It is interesting to note that fractions of BRBs induced different changes in gut bacteria compared to whole BRBs. The abundance of specific microbial species known to have anti-inflammatory effects, such as Akkermansia and Desulfovibrio, was increased by whole BRBs and their residue. Further, butyrate-producing bacteria, e.g., Anaerostipes, were increased by whole BRBs. Our results suggest that whole BRBs and their fractions alter the gut microbiota in ways that could significantly influence human health.
PMID: 28718724 [PubMed - as supplied by publisher]
from Cancer via ola Kala on Inoreader http://ift.tt/2uKQf0C
via IFTTT
Partial Substitution of Glucose with Xylitol Suppressed the Glycolysis and Selectively Inhibited the Proliferation of Oral Cancer Cells.
| Related Articles |
Partial Substitution of Glucose with Xylitol Suppressed the Glycolysis and Selectively Inhibited the Proliferation of Oral Cancer Cells.
Nutr Cancer. 2017 Jul 18;:1-11
Authors: Trachootham D, Chingsuwanrote P, Yoosadiang P, Mekkriangkrai D, Ratchawong T, Buraphacheep N, Kijanukul S, Saekhow S, Pongpitchayadej O, Vongvachvasin K, Sittikornpaiboon P, Tuntipopipat S
Abstract
Suitable diet for cancer survivors remains an unresolved challenge. Increased glucose utilization is a hallmark of various cancers. Therefore, alternative carbohydrate supplying normal tissue but retarding cancer growth is needed. This study investigated the effect of sugar alcohols on the proliferation of oral cancer cells compared to nontransformed cells and explored the mechanism. Six oral squamous cell carcinoma (CAL-27, FaDu, SCC4, SCC9, SCC15, and SCC25) and one nontransformed oral keratinocyte (OKF6/TERT2) lines were cultured in media containing 1 mg/ml glucose and 5.8 mg/ml xylitol or sorbitol, yielding equal energy input to control group (4.5 mg/ml glucose). Partial substitution of glucose with sugar alcohols especially xylitol significantly suppressed proliferation of oral cancer but not nontransformed cells. Despite the addition of isocaloric quantities of the sugars, cancer cells exposed to low glucose plus xylitol had retarded ATP generation and decreased activity of phosphofructokinase (PFK), the rate-limiting enzyme in glycolysis. Furthermore, D-xylulose, its key metabolic intermediate, enhanced the anticancer effect of xylitol. These findings suggested a selective anticancer activity of xylitol and the potential mechanism involving inhibition of glucose utilization. Partial substitution of glucose with xylitol may be a proper nutrient for oral cancer survivors, deserving further investigation in animal and clinical settings.
PMID: 28718681 [PubMed - as supplied by publisher]
from Cancer via ola Kala on Inoreader http://ift.tt/2uKMkB1
via IFTTT
Anticarcinogenic Effects of Dried Citrus Peel in Colon Carcinogenesis Due to Inhibition of Oxidative Stress.
| Related Articles |
Anticarcinogenic Effects of Dried Citrus Peel in Colon Carcinogenesis Due to Inhibition of Oxidative Stress.
Nutr Cancer. 2017 Jul 18;:1-7
Authors: Onuma W, Asai D, Tomono S, Miyamoto S, Fujii G, Hamoya T, Nagano A, Takahashi S, Masumori S, Miyoshi N, Wakabayashi K, Mutoh M
Abstract
Colorectal cancer is one of the leading causes of death worldwide. Reactive oxygen species produce oxidative stress and contribute to colorectal carcinogenesis. Because dietary citrus has been shown to reduce oxidative stress, we investigated the effects of citrus peel extract at dilutions of 1/200-1/500 on the activity of oxidative-stress-related transcription factors, including AP-1, NF-κB, NRF2, p53, and STAT3, in human colon cancer cell line HCT116 cells using a luciferase reporter gene assay. NRF2 transcriptional activities were 1.8- to 2.0-fold higher than the untreated control value. In addition, NF-κB, p53, and STAT3 transcriptional activities were 12-26% lower than the untreated control value. Administration of dried citrus peel in the diet of F344 rats at a dose of 1,000 ppm prevented the formation of azoxymethane-induced precancerous aberrant crypt foci (ACF) in the colon. The total number of ACF in rats fed with dried citrus peel was reduced to 75% of the control value. Moreover, the levels of oxidative-stress-related markers, reactive carbonyl species, in the serum of F344 rats were significantly reduced following the administration of dried citrus peel. These data suggest that citrus peel possesses an ability to suppress cellular oxidative stress through induction of NRF2, thereby preventing azoxymethane-induced colon carcinogenesis.
PMID: 28718722 [PubMed - as supplied by publisher]
from Cancer via ola Kala on Inoreader http://ift.tt/2uKFf31
via IFTTT
Association Between a Dietary Inflammatory Index and Prostate Cancer Risk in Ontario, Canada.
| Related Articles |
Association Between a Dietary Inflammatory Index and Prostate Cancer Risk in Ontario, Canada.
Nutr Cancer. 2017 Jul 18;:1-8
Authors: Shivappa N, Miao Q, Walker M, Hébert JR, Aronson KJ
Abstract
BACKGROUND: Evidence exists showing that various aspects of diet are implicated in the etiology of prostate cancer, although results across studies remain inconsistent.
METHODS: We examined the ability of the dietary inflammatory index (DII) to predict prostate cancer in a case-control study conducted in Kingston, Ontario, Canada, between 1997 and 1999. The study included 72 cases of incident primary prostate cancer patients and 302 controls of urology clinic patients who had prostate conditions other than prostate cancer. The DII was computed based on intake of 18 nutrients assessed using a 67-item food frequency questionnaire. Univariate and multivariate logistic regression models were used to estimate odds ratios (ORs).
RESULTS: Men with higher DII scores were at increased risk of prostate cancer using DII score fit both as a continuous [OR = 1.58, 95% confidence interval (CI) 1.05-2.38] and categorical variable [compared to men in the lowest DII quartile, men in the highest quartile were at elevated risk (OR = 3.50, 95% CI 1.25-9.80; ptrend = 0.02)]. There was no significant heterogeneity by weight status, but stronger association was observed in men with body mass index >25 kg/m(2) versus <25 kg/m(2).
CONCLUSION: These findings suggest that a proinflammatory diet, as indicated by increasing DII score, is a risk factor for prostate cancer.
PMID: 28718711 [PubMed - as supplied by publisher]
from Cancer via ola Kala on Inoreader http://ift.tt/2uKQ0Ta
via IFTTT
Evaluation of the Cytotoxic Activity of Crocin and Safranal, Constituents of Saffron, in Oral Squamous Cell Carcinoma (KB Cell Line).
| Related Articles |
Evaluation of the Cytotoxic Activity of Crocin and Safranal, Constituents of Saffron, in Oral Squamous Cell Carcinoma (KB Cell Line).
Nutr Cancer. 2017 Jul 18;:1-9
Authors: Jabini R, Ehtesham-Gharaee M, Dalirsani Z, Mosaffa F, Delavarian Z, Behravan J
Abstract
Crocin and safranal are active ingredients in the saffron. Some studies have demonstrated antitumor activities of saffron ingredients. The aim of this study was to evaluate cytotoxic effects of crocin and safranal in oral squamous cell carcinoma (KB cells) and NIH 3T3 cell line as nonmalignant cells. The cells were incubated with crocin and safranal at 37°C for 24, 48, and 72 h, and cell viability was quantitated by MTT assay. Apoptotic cells, cell cycle distribution, and sub-G1 fraction were determined using propidium iodide staining of DNA fragmentation by flow cytometry. Crocin (0.05-4 mM) and safranal (0.2-3.2 mM) significantly inhibited the growth of KB cells (the inhibitory growth effects of all concentrations for both were >50% after 72 h), while they had less inhibitory effects on NIH 3T3 cells viability. The IC50 values of crocin and safranal against NIH 3T3 cells after 72 h were determined as 2.8 and 0.3 mM, respectively. Crocin and safranal induced a sub-G1 peak in the flow cytometry histogram of treated cells compared to control cells indicating that apoptotic cell death is involved in the toxicity of crocin and safranal. Apoptotic effects of crocin and safranal in tumor cells were more than normal cells. Neither crocin nor safranal affected the cell cycle progression. Crocin and safranal exerted apoptotic effects in KB cell line.
PMID: 28718677 [PubMed - as supplied by publisher]
from Cancer via ola Kala on Inoreader http://ift.tt/2ts2kay
via IFTTT
Salvia fruticosa Modulates mRNA Expressions and Activity Levels of Xenobiotic Metabolizing CYP1A2, CYP2E1, NQO1, GPx, and GST Enzymes in Human Colorectal Adenocarcinoma HT-29 Cells.
| Related Articles |
Salvia fruticosa Modulates mRNA Expressions and Activity Levels of Xenobiotic Metabolizing CYP1A2, CYP2E1, NQO1, GPx, and GST Enzymes in Human Colorectal Adenocarcinoma HT-29 Cells.
Nutr Cancer. 2017 Jul 18;:1-12
Authors: Altay A, Bozoğlu F
Abstract
Natural products have gained considerable interests because of their use in some industrial areas including nutrition, cosmetic, pharmacy, and medicine. Salvia fruticosa M. (Lamiaceae) is known for its antioxidant, antimicrobial, and antiproliferative activities. Phase I xenobiotic metabolizing enzymes, CYP1A2 and CYP2E1, produce reactive metabolites which are eliminated by the action of phase II enzymes, NQO1, GPx, and glutathione S-transferases (GSTs). In this study, in vitro modulatory effects of S. fruticosa and its major phenolic compound rosmarinic acid (RA) on CYP1A2, CYP2E1, NQO1, GPx, and GSTm1 mRNA expressions and enzyme activities of GPx and GSTs were investigated in HT-29 cells. An mRNA expression analysis revealed that CYP1A2 and CYP2E1 levels were decreased while those of NQO1, GPx, and GSTm1 increased after S. fruticosa and RA treatments. In parallel to gene expressions, enzyme activities of GPx and GSTs by S. fruticosa increased 1.68- and 1.48-fold, respectively. Moreover, RA increased GPx and GSTs activities 1.67- and 1.94-fold, respectively. The results of this preliminary study show that metabolism of xenobiotics may be altered due to changes in the expression and activity of the investigated enzymes by S. fruticosa.
PMID: 28718679 [PubMed - as supplied by publisher]
from Cancer via ola Kala on Inoreader http://ift.tt/2trVYbn
via IFTTT
Dietary Inflammatory Index and Renal Cell Carcinoma Risk in an Italian Case-Control Study.
| Related Articles |
Dietary Inflammatory Index and Renal Cell Carcinoma Risk in an Italian Case-Control Study.
Nutr Cancer. 2017 Jul 18;:1-7
Authors: Shivappa N, Hébert JR, Rosato V, Rossi M, Montella M, Serraino D, La Vecchia C
Abstract
BACKGROUND: The relation between diet-related inflammation and renal cell carcinoma (RCC) has not been investigated.
METHODS: In this study, we explored the association between the dietary inflammatory index (DII) and RCC in an Italian case-control study conducted between 1992 and 2004. Cases were 767 patients with incident, histologically confirmed RCC. Controls were 1534 subjects admitted to the same hospitals as cases for various acute, nonneoplastic conditions. The DII was computed based on dietary intake assessed using a reproducible and valid 78-item food frequency questionnaire. Odds ratios (ORs) were estimated through logistic regression models conditioned on age, sex, and center, and adjusted for recognized confounding factors, including total energy intake.
RESULTS: Subjects in the highest quartile of DII scores (i.e., with the most proinflammatory diets) had a higher risk of RCC compared to subjects in the lowest quartile [OR 1.41, 95% confidence interval (CI) 1.02, 1.97; p-trend = 0.04)]. Apparently stronger associations were observed among females (OR 1.68, 95% CI 0.93, 3.03), subjects aged <60 yr (OR 1.77, 95% CI 1.05, 2.98), body mass index ≥25 kg/m(2) (OR 1.64, 95% CI 1.07, 2.51), and ever smokers (OR 1.66, 95% CI 1.08, 2.57), in the absence of significant heterogeneity.
CONCLUSION: A proinflammatory diet is associated with increased RCC risk.
PMID: 28718670 [PubMed - as supplied by publisher]
from Cancer via ola Kala on Inoreader http://ift.tt/2ts4qY3
via IFTTT
Fruit Peel Polyphenolic Extract-Induced Apoptosis in Human Breast Cancer Cells Is Associated with ROS Production and Modulation of p38MAPK/Erk1/2 and the Akt Signaling Pathway.
| Related Articles |
Fruit Peel Polyphenolic Extract-Induced Apoptosis in Human Breast Cancer Cells Is Associated with ROS Production and Modulation of p38MAPK/Erk1/2 and the Akt Signaling Pathway.
Nutr Cancer. 2017 Jul 18;:1-12
Authors: Kello M, Kulikova L, Vaskova J, Nagyova A, Mojzis J
Abstract
Polyphenols represent a large group of natural substances with different biological properties. Currently, polyphenols are well studied due to their free radicals' scavenging and antioxidant activities. However, some studies indicate that polyphenols also exhibit pro-oxidant properties. In this study, the possible involvement of the pro-oxidant activities of fruit polyphenols was investigated in relation to apoptosis induction. To determine the type of cell death induced by fruit polyphenols (Flavine; F7), we assessed a series of assays, including measurements of caspase-7 activation, membrane mitochondrial potential changes, reactive oxygen (ROS) and nitrogen species production, lipid peroxidation, antioxidant enzymes activities, and PARP cleavage. Moreover, the effect of F7 on selected pro- and antisurvival signaling pathways was determined. We demonstrated that fruit polyphenols induced caspase-dependent cell death associated with increased oxidative stress. We also showed fruit polyphenol-mediated release of mitochondrial pro- and antiapoptotic proteins of the Bcl-2 family and modulation activity of the Akt, p38 MAPK, and Erk 1/2 pathways as well as the signaling of ROS-mediated DNA damage. Our data demonstrated that fruit peel polyphenols suppressed breast cancer cell growth through increased intracellular oxidative stress and the activation of p38 MAPK and de-activation of the Erk 1/2 and Akt signaling pathways.
PMID: 28718669 [PubMed - as supplied by publisher]
from Cancer via ola Kala on Inoreader http://ift.tt/2trZpPe
via IFTTT
Olea europaea Leaf Extract Improves the Efficacy of Temozolomide Therapy by Inducing MGMT Methylation and Reducing P53 Expression un Glioblastoma.
| Related Articles |
Olea europaea Leaf Extract Improves the Efficacy of Temozolomide Therapy by Inducing MGMT Methylation and Reducing P53 Expression un Glioblastoma.
Nutr Cancer. 2017 Jul 18;:1-8
Authors: Tezcan G, Tunca B, Demirci H, Bekar A, Taskapilioglu MO, Kocaeli H, Egeli U, Cecener G, Tolunay S, Vatan O
Abstract
Unmethylated O6-methylguanine-DNA-methyltransferase (MGMT) promoter leads to Temozolomide (TMZ) resistance in most of the glioblastoma multiforme (GBM) patients. We previously investigated the synergistic effect of Olea europaea leaf extract (OLE) on TMZ cytotoxicity through modulating microRNA expression. To date, knowledge about the effect of OLE on MGMT methylation is insufficient. The aim of the current study was to evaluate the potential modulating effect of OLE on the TMZ response of GBM tumors through MGMT methylation. Exposure to 1 mg/mL OLE caused a significant induction of CpG island methylation in the MGMT gene using Methyl quantitative PCR assay (P < 0.001). In WST-1 analysis, the use of 350 µM TMZ plus 1 mg/mL OLE significantly increased the TMZ response of MGMT unmethylated cells (P = 0.003). Using the comet assay, the impact of 1 mg/mL OLE plus 350 µM TMZ on the formation of DNA strand breaks was significantly higher than that of 450 µM TMZ alone (P < 0.001) and Western blot analysis revealed that, when cells are treated with 1-mg/mL OLE, the total p53 protein levels tended to decrease. The results presented in this study uniquely demonstrated that OLE synergistically increased the TMZ response of GBM tumors by regulating MGMT gene methylation and p53 expression. However, further studies to validate our findings are required.
PMID: 28718668 [PubMed - as supplied by publisher]
from Cancer via ola Kala on Inoreader http://ift.tt/2trRTnA
via IFTTT
Hydroxytyrosol Induces Apoptosis and Cell Cycle Arrest and Suppresses Multiple Oncogenic Signaling Pathways in Prostate Cancer Cells.
| Related Articles |
Hydroxytyrosol Induces Apoptosis and Cell Cycle Arrest and Suppresses Multiple Oncogenic Signaling Pathways in Prostate Cancer Cells.
Nutr Cancer. 2017 Jul 18;:1-11
Authors: Zubair H, Bhardwaj A, Ahmad A, Srivastava SK, Khan MA, Patel GK, Singh S, Singh AP
Abstract
SCOPE: Hydroxytyrosol (HT), a polyphenol from olives, is a potential anticancer agent. This study was designed to evaluate the anticancer activity of HT against prostate cancer cells, and the mechanism thereof.
METHODS AND RESULTS: Treatment of LNCaP and C4-2 prostate cancer cells with HT resulted in a dose-dependent inhibition of proliferation. This was in contrast to HT's ineffectiveness against normal prostate epithelial cells RWPE1 and PWLE2, suggesting cancer-cell-specific effect. HT induced G1/S cell cycle arrest, with inhibition of cyclins D1/E and cdk2/4 and induction of inhibitory p21/p27. HT also induced apoptosis, as confirmed by flow cytometry, caspase activation, PARP cleavage, and BAX/Bcl-2 ratio. It inhibited the phosphorylation of Akt/STAT3, and induced cytoplasmic retention of NF-κB, which may explain its observed effects. Finally, HT inhibited androgen receptor (AR) expression and the secretion of AR-responsive prostate-specific antigen.
CONCLUSION: Castration-resistant prostate cancers retain AR signaling and are often marked by activated Akt, NF-κB, and STAT3 signaling. Our results establish a pleiotropic activity of HT against these oncogenic signaling pathways. Combined with its nontoxic effects against normal cells, our results support further testing of HT for prostate cancer therapy.
PMID: 28718667 [PubMed - as supplied by publisher]
from Cancer via ola Kala on Inoreader http://ift.tt/2tsjuVL
via IFTTT
Prevalence of Low Vitamin D in Patients with Breast Cancer in a Predominantly Hispanic Population at the American-Mexican Border.
| Related Articles |
Prevalence of Low Vitamin D in Patients with Breast Cancer in a Predominantly Hispanic Population at the American-Mexican Border.
Nutr Cancer. 2017 Jul 18;:1-6
Authors: Farrag SE, Dwivedi AK, Otoukesh S, Badri NJ, Sanchez LA, Nahleh ZA
Abstract
INTRODUCTION: Low level of vitamin D (VD) has been linked with a higher risk of cancers. The aim of this study was to assess the prevalence of low VD in patients with breast cancer in a predominantly Mexican Hispanic/Latino patient population, a fast growing and relatively understudied population.
MATERIALS/METHODS: We sought to evaluate the serum VD levels in breast cancer patients diagnosed at the Texas Tech University Breast Cancer Center in El Paso, TX, between May 2013 and May2014 via a retrospective chart review of the Electronic Medical Records.
RESULTS: We identified a total of 83 consecutive breast cancer patients with available VD levels. Mean age 57 yr, 94% were Hispanics. VD was insufficient (<30 ng/ml) in 86% of patients (95% CI: 0.76-0.92) and it was deficient (<20 ng/ml) in 39% (95% CI: 0.28-0.50).
CONCLUSION: VD deficiency is widely prevalent in Hispanic/Latino patients with breast cancer. This is quite alarming in view of possible increased risk of cancer with low VD and potentially worse cancer outcomes. This calls for increased efforts to screen for, diagnose, and treat VD deficiency in this patient population. Further pharmacogenomics studies are warranted to explore the underlying etiology of VD deficiency in this paradoxically sunny region.
PMID: 28718665 [PubMed - as supplied by publisher]
from Cancer via ola Kala on Inoreader http://ift.tt/2trSd5x
via IFTTT
The transcription factor Olig2 is important for the biology of diffuse intrinsic pontine gliomas
Abstract
Background.
Diffuse intrinsic pontine glioma (DIPG) is a high-grade brainstem glioma of children with dismal prognosis. There is no single unifying model about the cell of origin of DIPGs. Proliferating cells in the developing human and mouse pons, the site of DIPGs, express neural stem/progenitor cell (NPC) markers, including Sox2, nestin, vimentin, Olig2, and glial fibrillary acidic protein, in an overlapping and non-overlapping manner, suggesting progenitor cell heterogeneity in the pons. It is thought that during a restricted window of postnatal pons development, a differentiation block caused by genetic/epigenetic changes leads to unrestrained progenitor proliferation and DIPG development. Nearly 80% of DIPGs harbor a mutation in the H3F3A or the related HIST1H3B gene. Supporting the impaired differentiation model, NPCs derived from human induced pluripotent stem cells expressing the H3F3A mutation showed complete differentiation block. However, the mechanisms regulating an altered differentiation program in DIPG are unknown. Methods.
We established syngeneic serum-dependent and independent primary DIPG lines, performed molecular characterization of DIPG lines in vitro and in an orthotopic xenograft model, and used small hairpin RNA to examine Olig2 function in DIPG. Results.
The transcription factor Olig2 is highly expressed in 70%–80% of DIPGs. Here we report that Olig2 expression and DIPG differentiation are mutually exclusive events in vitro, and only DIPG cells that retained Olig2 in vitro formed robust Olig2-positive brainstem glioma with 100% penetrance in a xenograft model. Conclusion.
Our results indicate Olig2 as an onco-requisite factor in DIPG and propose investigation of Olig2 target genes as novel candidates in DIPG therapy.http://ift.tt/2uJwmai
Prophylactic cranial irradiation in patients with extensive-stage small cell lung cancer
Brain metastases occur in the majority of patients with small cell lung cancer (SCLC).1 The blood–brain barrier prevents sufficient entry of most chemotherapeutic agents into the brain,2 and once brain metastases are visible radiographically, few patients remain curable. The very high prevalence of brain metastases in patients with SCLC combined with the poor intracranial penetration of most chemotherapy regimens used in the disease and the potential curability of such patients led to the development and utilization of prophylactic cranial irradiation (PCI), a preventative radiotherapeutic treatment of the entire brain targeting subclinical intracranial metastatic disease.
http://ift.tt/2uJIms2
http://ift.tt/2uJIms2
Frequent AKT1 E17K mutations in skull base meningiomas are associated with mTOR and ERK1/2 activation and reduced time to tumor recurrence
Abstract
Background.
Skull base meningiomas are considered to be difficult for surgical treatment. We wondered whether genetic alterations recently identified in benign non-NF2-mutated World Health Organization (WHO) grade I meningiomas are related to clinical features of skull base meningiomas and whether druggable signaling pathways are activated. Methods.
We analyzed 93 skull base meningiomas (82 WHO grade I, 11 WHO grade II) for mutations of hot spots or the most relevant exons of AKT1, KLF4/TRAF7, SMO, PI3K, and the TERT promoter. Results.
The AKT1E17K mutation was present in 31% of patients and was related to meningothelial histology. AKT1E17K had a negative effect on the time to tumor recurrence. Analyses of activated signaling proteins revealed among AKT1E17K tumors a significantly higher rate of phospho–mammalian target of rapamycin (mTOR) and phospho-p70S6K+ tumors. AKT1E17K tumors with immunoexpression of phospho–extracellular signal-regulated kinase 1 or 2 (ERK1/2) were characterized by significantly shorter time to tumor recurrence compared with AKT1wt tumors expressing phospho-ERK1/2 (P = .046). KLF4 mutations (K409Q) were present in 11.8% of cases, with significant association to the secretory/transitional subtype (P < .001). The presence of the KLF4 K409Q mutation was associated with favorable outcome. One phosphatidylinositol-3 kinase (PI3K) mutation but no SMO or TERT promoter mutation was found. Conclusions.
AKT1E17K mutation is frequent in skull base meningiomas, results in activation of the mTOR and ERK1/2 signaling pathways, and has negative impact on tumor recurrence. Patients with skull base meningiomas with AKT1E17K mutation might benefit from additional treatment targeting the mTOR pathway. Generally, the PI3K-Akt-mTOR axis might be a potential target for kinase inhibitors in these tumors.http://ift.tt/2uJAiaZ
The radiosensitivity of brain metastases based upon primary histology utilizing a multigene index of tumor radiosensitivity
A number of retrospective and prospective series have assessed local control outcomes of brain metastases based on primary histology.1–4 These studies have revealed mixed results, with some studies showing poorer local control with histologies typically classified as radioresistant, including melanoma and renal cell cancers. The current determinants of stereotactic radiation dose are lesion size and receipt of previous radiation treatment.5 Histology does not routinely play a primary role in the determination of radiation dose.
http://ift.tt/2uJywX7
http://ift.tt/2uJywX7
Mutational burden, immune checkpoint expression, and mismatch repair in glioma: implications for immune checkpoint immunotherapy
Abstract
Background.
Despite a multiplicity of clinical trials testing immune checkpoint inhibitors, the frequency of expression of potential predictive biomarkers is unknown in glioma. Methods.
In this study, we profiled the frequency of shared biomarker phenotypes. To clarify the relationships among tumor mutational load (TML), mismatch repair (MMR), and immune checkpoint expression, we profiled patients with glioma (n = 327), including glioblastoma (GBM) (n = 198), whose samples had been submitted for analysis from 2009 to 2016. The calculation algorithm for TML included nonsynonymous mutation counts per tumor, with germline mutations filtered out. Immunohistochemical analysis and next-generation sequencing were used to determine tumor-infiltrating lymphocyte expression positive for programmed cell death protein 1 (PD-1), PD ligand 1 (PD-L1) expression on tumor cells, MMR (MLH1, MSH2, MSH6, and PMS2) protein expression and mutations, and DNA polymerase epsilon (POLE) mutations. Results.
High TML was only found in 3.5% of GBM patients (7 of 198) and was associated with the absence of protein expression of mutL homolog 1 (MLH1) (P = .0345), mutS homolog 2 (MSH2) (P = .0099), MSH6 (P = .0022), and postmeiotic segregation increased 2 (PMS2) (P = .0345) and the presence of DNA MMR mutations. High and moderate TML GBMs did not have an enriched influx of CD8+ T cells, PD-1+ T cells, or tumor-expressed PD-L1. IDH1 mutant gliomas were not enriched for high TML, PD-1+ T cells, or PD-L1 expression. Conclusions.
To clarify the relationships among TML, MMR, and immune checkpoint expression, we profiled the frequency of shared biomarker phenotypes. On the basis of a variety of potential biomarkers of response to immune checkpoints, only small subsets of glioma patients are likely to benefit from monotherapy immune checkpoint inhibition.http://ift.tt/2vjDN4P
Diffuse intrinsic pontine gliomas—current management and new biologic insights. Is there a glimmer of hope?
Abstract
Diffuse intrinsic pontine glioma (DIPG) has proven to be one of the most challenging of all pediatric cancers. Owing to a historical reticence to obtain tumor tissue for study, and based on an erroneous assumption that the biology of DIPG would mirror that of supratentorial high-grade astrocytomas, innumerable studies have been undertaken—all of which have had a negligible impact on the natural history of this disease. More recently, improvements in neurosurgical techniques have allowed for the safe upfront biopsy of DIPG, which, together with a wider use of autopsy tissue, has led to an evolving understanding of the biology of this tumor. The discovery of a recurrent somatic gain-of-function mutation leading to lysine 27 to methionine (p.Lys27Met, K27M) substitution in histone 3 variants characterizes more than 85% of DIPG, suggesting for the first time the role of the epigenome and histones in the pathogenesis of this disease, and more unified diagnostic criteria. Along with further molecular insights into the pathogenesis of DIPG, rational targets are being identified and studied in the hopes of improving the otherwise dismal outcome for children with DIPG.http://ift.tt/2uJk0ip
Is more better? The impact of extended adjuvant temozolomide in newly diagnosed glioblastoma: a secondary analysis of EORTC and NRG Oncology/RTOG
Abstract
Background:
Radiation with concurrent and adjuvant (6 cycles) temozolomide (TMZ) is the established standard of postsurgical care for newly diagnosed glioblastoma (GBM). This regimen has been adopted with variations, including extending TMZ beyond 6 cycles. The optimal duration of maintenance therapy remains controversial. Methods:
We performed pooled analysis of individual patient data from 4 randomized trials for newly diagnosed GBM. All patients who were progression free 28 days after cycle 6 were included. The decision to continue TMZ was per local practice and standards, and at the discretion of the treating physician. Patients were grouped into those treated with 6 cycles and those who continued beyond 6 cycles. Progression-free and overall survival were compared, adjusted by age, performance status, resection extent, and MGMT methylation. Results:
A total of 2214 GBM patients were included in the 4 trials. Of these, 624 qualified for analysis 291 continued maintenance TMZ until progression or up to 12 cycles, while 333 discontinued TMZ after 6 cycles. Adjusted for prognostic factors, treatment with more than 6 cycles of TMZ was associated with a somewhat improved progression-free survival (hazard ratio [HR] 0.80 [0.65–0.98], P = .03), in particular for patients with methylated MGMT (n = 342, HR 0.65 [0.50–0.85], P < .01). However, overall survival was not affected by the number of TMZ cycles (HR = 0.92 [0.71–1.19], P = .52), including the MGMT methylated subgroup (HR = 0.89 [0.63–1.26], P = .51). Conclusions:
Continuing TMZ beyond 6 cycles was not shown to increase overall survival for newly diagnosed GBM.http://ift.tt/2vjLBU9
Repositioning disulfiram as a radiosensitizer against atypical teratoid/rhabdoid tumor
Abstract
Background.
Atypical teratoid/rhabdoid tumor (AT/RT) is one of the most common malignant brain tumors in infants. Although cancer stem cells of AT/RT express aldehyde dehydrogenase (ALDH), effective chemotherapies against AT/RT have not been established. Here, we examined radiosensitizing effects of disulfiram (DSF), an irreversible inhibitor of ALDH against AT/RT for a novel therapeutic method. Methods.
Patient-derived primary cultured AT/RT cells (SNU.AT/RT-5 and SNU.AT/RT-6) and established AT/RT cell lines (BT-12 and BT-16) were used to assess therapeutic effects of combining DSF with radiation treatment (RT). Survival fraction by clonogenic assay, protein expression, immunofluorescence, and autophagy analysis were evaluated in vitro. Antitumor effects of combining DSF with RT were verified by bioluminescence imaging, tumor volume, and survival analysis in vivo. Results.
The results demonstrated that DSF at low concentration enhanced the radiosensitivity of AT/RT cells with reduction of survival fraction to 1.21‒1.58. DSF increased DNA double-strand break (γ-H2AX, p-DNA-PKcs, and p-ATM), apoptosis (cleaved caspase-3), autophagy (LC3B), and cell cycle arrest (p21) in irradiated AT/RT cells, while it decreased anti-apoptosis (nuclear factor-kappaB, Survivin, and B-cell lymphoma 2 [Bcl2]). In vivo, DSF and RT combined treatment significantly reduced tumor volumes and prolonged the survival of AT/RT mouse models compared with single treatments. The combined treatment also increased γ-H2AX, cleaved caspase-3, and LC3B expression and decreased ALDH1, Survivin, and Bcl2 expression in vivo. Conclusions.
DSF and RT combination therapy has additive therapeutic effects on AT/RT by potentiating programmed cell death, including apoptosis and autophagy of AT/RT cells. We suggest that DSF can be applied as a radiosensitizer in AT/RT treatment.http://ift.tt/2uJI0BS
Sleep disturbance of adults with a brain tumor and their family caregivers: a systematic review
Abstract
The high incidence and psychophysiological morbidities of sleep disturbance in cancer have been increasingly recognized. Yet, more detailed understanding of sleep disturbance and options for management have been neglected areas in both clinical care and research. Brain tumor patients have been particularly overlooked. A systematic search of the literature from 1990 to 2015 was performed to review sleep disturbance in adults with primary or secondary brain tumor and their family caregivers. Fifty eligible studies were identified, of which 12 focused on sleep, 37 reported sleep items within a health-related quality of life measure and 1 reported caregivers' sleep. No sleep intervention has been developed or tested for brain tumor patients. Sleep disturbance and somnolence were frequently reported as the most severely rated symptoms within health-related quality of life across the disease course or treatments, along with fatigue. However, sleep-focused studies yielded inconsistent results in small samples of mostly benign brain tumors in long-term remission from total tumor resection. The research using standardized, multifaceted sleep assessments, particularly in patients with malignant brain tumor and caregivers who are undergoing treatment, is seriously lacking. A more systematic examination of sleep disturbance is warranted to inform the development of better symptom management programs in this population.http://ift.tt/2vjpIEH
Glioblastoma stem cell differentiation into endothelial cells evidenced through live-cell imaging
Abstract
Background.
Glioblastoma cell-initiated vascularization is an alternative angiogenesis called vasculogenic mimicry. However, current knowledge on the mechanism of de novo vessel formation from glioblastoma stem cells (GSCs) is limited. Methods.
Sixty-four glioblastoma samples from patients and 10 fluorescent glioma xenograft samples were examined by immunofluorescence staining for endothelial marker (CD34 and CD31) and glial cell marker (glial fibrillary acidic protein [GFAP]) expression. GSCs were then isolated from human glioblastoma tissue and CD133+/Sox2+ red fluorescent protein-containing (RFP)–GSC-1 cells were established. The ability of these cells to form vascular structures was examined by live-cell imaging of 3D cultures. Results.
CD34-GFAP or CD31-GFAP coexpressing glioblastoma-derived endothelial cells (GDEC) were found in 30 of 64 (46.9%) of clinical glioblastoma samples. In those 30 samples, GDEC were found to form vessel structures in 21 (70%) samples. Among 21 samples with GDEC vessels, the CD34+ GDEC vessels and CD31+ GDEC vessels accounted for about 14.16% and 18.08% of total vessels, respectively. In the xenograft samples, CD34+ GDEC were found in 7 out of 10 mice, and 4 out of 7 mice had CD34+ GDEC vessels. CD31+ GDEC were also found in 7 mice, and 4 mice had CD31+ GDEC vessels (10 mice in total). Through live-cell imaging, we observed gradual CD34 expression when cultured with vascular endothelial growth factor in some glioma cells, and a dynamic increase in endothelial marker expression in RFP–GSC-1 in vitro was recorded. Cells expressed CD34 (9.46%) after 6 hours in culture. Conclusions.
The results demonstrated that GSCs may differentiate into endothelial cells and promote angiogenesis in glioblastomas.http://ift.tt/2uJAwib
A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study
Abstract
Background.
Activation of the mitogen-activated protein kinase pathway is important for growth of pediatric low-grade gliomas (LGGs). The aim of this study was to determine the recommended phase II dose (RP2D) and the dose-limiting toxicities (DLTs) of the MEK inhibitor selumetinib in children with progressive LGG. Methods.
Selumetinib was administered orally starting at 33 mg/m2/dose b.i.d., using the modified continual reassessment method. Pharmacokinetic analysis was performed during the first course. BRAF aberrations in tumor tissue were determined by real-time polymerase chain reaction and fluorescence in situ hybridization. Results.
Thirty-eight eligible subjects were enrolled. Dose levels 1 and 2 (33 and 43 mg/m2/dose b.i.d.) were excessively toxic. DLTs included grade 3 elevated amylase/lipase (n = 1), headache (n = 1), mucositis (n = 2), and grades 2–3 rash (n = 6). At dose level 0 (25 mg/m2/dose b.i.d, the RP2D), only 3 of 24 subjects experienced DLTs (elevated amylase/lipase, rash, and mucositis). At the R2PD, the median (range) area under the curve (AUC0-∞) and apparent oral clearance of selumetinib were 3855 ng*h/mL (1780 to 7250 ng × h/mL) and 6.5 L × h−1 × m−2 (3.4 to 14.0 L × h−1 × m−2), respectively. Thirteen of 19 tumors had BRAF abnormalities. Among the 5 (20%) of 25 subjects with sustained partial responses, all at the RP2D, 4 had BRAF aberrations, 1 had insufficient tissue. Subjects received a median of 13 cycles (range: 1–26). Fourteen (37%) completed all protocol treatment (26 cycles [n = 13], 13 cycles [n = 1]) with at least stable disease; 2-year progression-free survival at the RP2D was 69 ± SE 9.8%. Conclusion.
Selumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs.http://ift.tt/2vkldcL
The clinical value of patient-derived glioblastoma tumorspheres in predicting treatment response
Abstract
Background.
Advances from glioma stemlike cell (GSC) research, though increasing our knowledge of glioblastoma (GBM) biology, do not influence clinical decisions yet. We explored the translational power of GSC-enriched cultures from patient-derived tumorspheres (TS) in predicting treatment response. Methods.
The relationship between TS growth and clinical outcome was investigated in 52 GBMs treated with surgical resection followed by radiotherapy and temozolomide (TMZ). The effect on TS of radiation (6 to 60 Gy) and of TMZ (3.9 μM to 1 mM) was related with patients' survival. Results.
Generation of TS was an independent factor for poor overall survival (OS) and poor progression-free survival (PFS) (P < .0001 and P = .0010, respectively). Growth rate and clonogenicity of TS predicted poor OS. In general, TS were highly resistant to both radiation and TMZ. Resistance to TMZ was stronger in TS with high clonogenicity and fast growth (P < .02). Shorter PFS was associated with radiation LD50 (lethal dose required to kill 50% of TS cells) >12 Gy of matched TS (P = .0484). A direct relationship was found between sensitivity of TS to TMZ and patients' survival (P = .0167 and P = .0436 for OS and PFS, respectively). Importantly, values for TMZ half-maximal inhibitory concentration <50 μM, which are in the range of plasma levels achieved in vivo, identified cases with longer OS and PFS (P = .0020 and P = .0016, respectively). Conclusions.
Analysis of TS holds translational relevance by predicting the response of parent tumors to radiation and, particularly, to TMZ. Dissecting the clonogenic population from proliferating progeny in TS can guide therapeutic strategies to a more effective drug selection and treatment duration.http://ift.tt/2vk8qHd
Evaluating the significance of density, localization, and PD-1/PD-L1 immunopositivity of mononuclear cells in the clinical course of lung adenocarcinoma patients with brain metastasis
Abstract
Background.
Management of lung cancer patients who suffer from brain metastases represents a major challenge. Considering the promising results with immune checkpoint inhibitor treatment, evaluating the status of immune cell (IC) infiltrates in the prognosis of brain metastasis may lead to better therapeutic strategies with these agents. The aim of this study was to characterize the distribution of ICs and determine the expression of the checkpoint molecules programmed death protein 1 (PD-1) and its ligand, PD-L1, in brain metastasis of lung adenocarcinoma (LUAD) patients and to analyze their clinicopathological correlations. Methods.
We determined the presence of peritumoral mononuclear cells (mononuclear ring) and the density of intratumoral stromal mononuclear cells on brain metastasis tissue sections of 208 LUAD patients. PD-L1/PD-1 expressions were analyzed by immunohistochemistry. Results.
Mononuclear rings were significantly associated with better survival after brain metastasis surgery. Cases with massive stromal IC infiltration also showed a tendency for better overall survival. Lower expression of PD-1 and PD-L1 was associated with better survival in patients who underwent surgery for the primary tumor and had multiple brain metastases. Steroid administration and chemotherapy appear not to influence the density of IC in brain metastasis. Conclusion.
This is the first study demonstrating the independent prognostic value of mononuclear rings in LUAD cases with brain metastasis. Our results also suggest that the density of tumor-associated ICs in addition to PD-L1 expression of tumor cells and ICs as well as PD-1 expression of ICs may hold relevant information for the appropriate selection of patients who might benefit from anti–PD-L1 or anti–PD-1 therapy.http://ift.tt/2uJAtD1
Characteristics of H3 K27M-mutant gliomas in adults
Abstract
Background.
Diffuse H3 K27M-mutant gliomas occur primarily in children but can also be encountered in adults. The aim of this study was to describe the characteristics of H3 K27M-mutant gliomas in adults. Methods.
We analyzed the characteristics of 21 adult H3 K27M-mutant gliomas and compared them with those of 135 adult diffuse gliomas without histone H3 and without isocitrate dehydrogenase (IDH) mutation (IDH/H3 wild type). Results.
The median age at diagnosis in H3 K27M-mutant gliomas was 32 years (range: 18–82 y). All tumors had a midline location (spinal cord n = 6, thalamus n = 5, brainstem n = 5, cerebellum n = 3, hypothalamus n = 1, and pineal region n = 1) and were IDH and BRAF-V600E wild type. The identification of an H3 K27M mutation significantly impacted the diagnosis in 3 patients (14%) for whom the histological aspect initially suggested a diffuse low-grade glioma and in 7 patients (33%) for whom pathological analysis hesitated between a diffuse glioma, ganglioglioma, or pilocytic astrocytoma. Compared with IDH/H3 wild-type gliomas, H3 K27M-mutant gliomas were diagnosed at an earlier age (32 vs 64 y, P < .001), always had a midline location (21/21 vs 21/130, P < .001), less frequently had a methylated MGMT promoter (1/21 vs 52/129, P = .002), and lacked EGFR amplification (0/21 vs 26/128, P = .02). The median survival was 19.6 months in H3 K27M-mutant gliomas and 17 months in IDH/H3 wild-type gliomas (P = .3). Conclusion.
In adults, as in children, H3 K27M mutations define a distinct subgroup of IDH wild-type gliomas characterized by a constant midline location, low rate of MGMT promoter methylation, and poor prognosis.http://ift.tt/2vjXSI6
Prophylactic cranial irradiation in patients with extensive-stage small cell lung cancer
Brain metastases occur in the majority of patients with small cell lung cancer (SCLC).1 The blood–brain barrier prevents sufficient entry of most chemotherapeutic agents into the brain,2 and once brain metastases are visible radiographically, few patients remain curable. The very high prevalence of brain metastases in patients with SCLC combined with the poor intracranial penetration of most chemotherapy regimens used in the disease and the potential curability of such patients led to the development and utilization of prophylactic cranial irradiation (PCI), a preventative radiotherapeutic treatment of the entire brain targeting subclinical intracranial metastatic disease.
from Cancer via ola Kala on Inoreader http://ift.tt/2uJIms2
via IFTTT
from Cancer via ola Kala on Inoreader http://ift.tt/2uJIms2
via IFTTT
A search for the “Goldilocks zone” with regard to the optimal duration of adjuvant temozolomide in patients with glioblastoma
See the article by Blumenthal et al on pages 1119–1126.
from Cancer via ola Kala on Inoreader http://ift.tt/2vjRe4E
via IFTTT
from Cancer via ola Kala on Inoreader http://ift.tt/2vjRe4E
via IFTTT
Lessons learned from diffuse intrinsic pontine glioma: how a terrible disease forced us to think better
See the article by Cohen et al on pages 1025–1034.
from Cancer via ola Kala on Inoreader http://ift.tt/2uJCkaY
via IFTTT
from Cancer via ola Kala on Inoreader http://ift.tt/2uJCkaY
via IFTTT
Frequent AKT1 E17K mutations in skull base meningiomas are associated with mTOR and ERK1/2 activation and reduced time to tumor recurrence
Abstract
Background.
Skull base meningiomas are considered to be difficult for surgical treatment. We wondered whether genetic alterations recently identified in benign non-NF2-mutated World Health Organization (WHO) grade I meningiomas are related to clinical features of skull base meningiomas and whether druggable signaling pathways are activated. Methods.
We analyzed 93 skull base meningiomas (82 WHO grade I, 11 WHO grade II) for mutations of hot spots or the most relevant exons of AKT1, KLF4/TRAF7, SMO, PI3K, and the TERT promoter. Results.
The AKT1E17K mutation was present in 31% of patients and was related to meningothelial histology. AKT1E17K had a negative effect on the time to tumor recurrence. Analyses of activated signaling proteins revealed among AKT1E17K tumors a significantly higher rate of phospho–mammalian target of rapamycin (mTOR) and phospho-p70S6K+ tumors. AKT1E17K tumors with immunoexpression of phospho–extracellular signal-regulated kinase 1 or 2 (ERK1/2) were characterized by significantly shorter time to tumor recurrence compared with AKT1wt tumors expressing phospho-ERK1/2 (P = .046). KLF4 mutations (K409Q) were present in 11.8% of cases, with significant association to the secretory/transitional subtype (P < .001). The presence of the KLF4 K409Q mutation was associated with favorable outcome. One phosphatidylinositol-3 kinase (PI3K) mutation but no SMO or TERT promoter mutation was found. Conclusions.
AKT1E17K mutation is frequent in skull base meningiomas, results in activation of the mTOR and ERK1/2 signaling pathways, and has negative impact on tumor recurrence. Patients with skull base meningiomas with AKT1E17K mutation might benefit from additional treatment targeting the mTOR pathway. Generally, the PI3K-Akt-mTOR axis might be a potential target for kinase inhibitors in these tumors.from Cancer via ola Kala on Inoreader http://ift.tt/2uJAiaZ
via IFTTT
The radiosensitivity of brain metastases based upon primary histology utilizing a multigene index of tumor radiosensitivity
A number of retrospective and prospective series have assessed local control outcomes of brain metastases based on primary histology.1–4 These studies have revealed mixed results, with some studies showing poorer local control with histologies typically classified as radioresistant, including melanoma and renal cell cancers. The current determinants of stereotactic radiation dose are lesion size and receipt of previous radiation treatment.5 Histology does not routinely play a primary role in the determination of radiation dose.
from Cancer via ola Kala on Inoreader http://ift.tt/2uJywX7
via IFTTT
from Cancer via ola Kala on Inoreader http://ift.tt/2uJywX7
via IFTTT
Mutational burden, immune checkpoint expression, and mismatch repair in glioma: implications for immune checkpoint immunotherapy
Abstract
Background.
Despite a multiplicity of clinical trials testing immune checkpoint inhibitors, the frequency of expression of potential predictive biomarkers is unknown in glioma. Methods.
In this study, we profiled the frequency of shared biomarker phenotypes. To clarify the relationships among tumor mutational load (TML), mismatch repair (MMR), and immune checkpoint expression, we profiled patients with glioma (n = 327), including glioblastoma (GBM) (n = 198), whose samples had been submitted for analysis from 2009 to 2016. The calculation algorithm for TML included nonsynonymous mutation counts per tumor, with germline mutations filtered out. Immunohistochemical analysis and next-generation sequencing were used to determine tumor-infiltrating lymphocyte expression positive for programmed cell death protein 1 (PD-1), PD ligand 1 (PD-L1) expression on tumor cells, MMR (MLH1, MSH2, MSH6, and PMS2) protein expression and mutations, and DNA polymerase epsilon (POLE) mutations. Results.
High TML was only found in 3.5% of GBM patients (7 of 198) and was associated with the absence of protein expression of mutL homolog 1 (MLH1) (P = .0345), mutS homolog 2 (MSH2) (P = .0099), MSH6 (P = .0022), and postmeiotic segregation increased 2 (PMS2) (P = .0345) and the presence of DNA MMR mutations. High and moderate TML GBMs did not have an enriched influx of CD8+ T cells, PD-1+ T cells, or tumor-expressed PD-L1. IDH1 mutant gliomas were not enriched for high TML, PD-1+ T cells, or PD-L1 expression. Conclusions.
To clarify the relationships among TML, MMR, and immune checkpoint expression, we profiled the frequency of shared biomarker phenotypes. On the basis of a variety of potential biomarkers of response to immune checkpoints, only small subsets of glioma patients are likely to benefit from monotherapy immune checkpoint inhibition.from Cancer via ola Kala on Inoreader http://ift.tt/2vjDN4P
via IFTTT
Diffuse intrinsic pontine gliomas—current management and new biologic insights. Is there a glimmer of hope?
Abstract
Diffuse intrinsic pontine glioma (DIPG) has proven to be one of the most challenging of all pediatric cancers. Owing to a historical reticence to obtain tumor tissue for study, and based on an erroneous assumption that the biology of DIPG would mirror that of supratentorial high-grade astrocytomas, innumerable studies have been undertaken—all of which have had a negligible impact on the natural history of this disease. More recently, improvements in neurosurgical techniques have allowed for the safe upfront biopsy of DIPG, which, together with a wider use of autopsy tissue, has led to an evolving understanding of the biology of this tumor. The discovery of a recurrent somatic gain-of-function mutation leading to lysine 27 to methionine (p.Lys27Met, K27M) substitution in histone 3 variants characterizes more than 85% of DIPG, suggesting for the first time the role of the epigenome and histones in the pathogenesis of this disease, and more unified diagnostic criteria. Along with further molecular insights into the pathogenesis of DIPG, rational targets are being identified and studied in the hopes of improving the otherwise dismal outcome for children with DIPG.from Cancer via ola Kala on Inoreader http://ift.tt/2uJk0ip
via IFTTT
Is more better? The impact of extended adjuvant temozolomide in newly diagnosed glioblastoma: a secondary analysis of EORTC and NRG Oncology/RTOG
Abstract
Background:
Radiation with concurrent and adjuvant (6 cycles) temozolomide (TMZ) is the established standard of postsurgical care for newly diagnosed glioblastoma (GBM). This regimen has been adopted with variations, including extending TMZ beyond 6 cycles. The optimal duration of maintenance therapy remains controversial. Methods:
We performed pooled analysis of individual patient data from 4 randomized trials for newly diagnosed GBM. All patients who were progression free 28 days after cycle 6 were included. The decision to continue TMZ was per local practice and standards, and at the discretion of the treating physician. Patients were grouped into those treated with 6 cycles and those who continued beyond 6 cycles. Progression-free and overall survival were compared, adjusted by age, performance status, resection extent, and MGMT methylation. Results:
A total of 2214 GBM patients were included in the 4 trials. Of these, 624 qualified for analysis 291 continued maintenance TMZ until progression or up to 12 cycles, while 333 discontinued TMZ after 6 cycles. Adjusted for prognostic factors, treatment with more than 6 cycles of TMZ was associated with a somewhat improved progression-free survival (hazard ratio [HR] 0.80 [0.65–0.98], P = .03), in particular for patients with methylated MGMT (n = 342, HR 0.65 [0.50–0.85], P < .01). However, overall survival was not affected by the number of TMZ cycles (HR = 0.92 [0.71–1.19], P = .52), including the MGMT methylated subgroup (HR = 0.89 [0.63–1.26], P = .51). Conclusions:
Continuing TMZ beyond 6 cycles was not shown to increase overall survival for newly diagnosed GBM.from Cancer via ola Kala on Inoreader http://ift.tt/2vjLBU9
via IFTTT
Repositioning disulfiram as a radiosensitizer against atypical teratoid/rhabdoid tumor
Abstract
Background.
Atypical teratoid/rhabdoid tumor (AT/RT) is one of the most common malignant brain tumors in infants. Although cancer stem cells of AT/RT express aldehyde dehydrogenase (ALDH), effective chemotherapies against AT/RT have not been established. Here, we examined radiosensitizing effects of disulfiram (DSF), an irreversible inhibitor of ALDH against AT/RT for a novel therapeutic method. Methods.
Patient-derived primary cultured AT/RT cells (SNU.AT/RT-5 and SNU.AT/RT-6) and established AT/RT cell lines (BT-12 and BT-16) were used to assess therapeutic effects of combining DSF with radiation treatment (RT). Survival fraction by clonogenic assay, protein expression, immunofluorescence, and autophagy analysis were evaluated in vitro. Antitumor effects of combining DSF with RT were verified by bioluminescence imaging, tumor volume, and survival analysis in vivo. Results.
The results demonstrated that DSF at low concentration enhanced the radiosensitivity of AT/RT cells with reduction of survival fraction to 1.21‒1.58. DSF increased DNA double-strand break (γ-H2AX, p-DNA-PKcs, and p-ATM), apoptosis (cleaved caspase-3), autophagy (LC3B), and cell cycle arrest (p21) in irradiated AT/RT cells, while it decreased anti-apoptosis (nuclear factor-kappaB, Survivin, and B-cell lymphoma 2 [Bcl2]). In vivo, DSF and RT combined treatment significantly reduced tumor volumes and prolonged the survival of AT/RT mouse models compared with single treatments. The combined treatment also increased γ-H2AX, cleaved caspase-3, and LC3B expression and decreased ALDH1, Survivin, and Bcl2 expression in vivo. Conclusions.
DSF and RT combination therapy has additive therapeutic effects on AT/RT by potentiating programmed cell death, including apoptosis and autophagy of AT/RT cells. We suggest that DSF can be applied as a radiosensitizer in AT/RT treatment.from Cancer via ola Kala on Inoreader http://ift.tt/2uJI0BS
via IFTTT
Sleep disturbance of adults with a brain tumor and their family caregivers: a systematic review
Abstract
The high incidence and psychophysiological morbidities of sleep disturbance in cancer have been increasingly recognized. Yet, more detailed understanding of sleep disturbance and options for management have been neglected areas in both clinical care and research. Brain tumor patients have been particularly overlooked. A systematic search of the literature from 1990 to 2015 was performed to review sleep disturbance in adults with primary or secondary brain tumor and their family caregivers. Fifty eligible studies were identified, of which 12 focused on sleep, 37 reported sleep items within a health-related quality of life measure and 1 reported caregivers' sleep. No sleep intervention has been developed or tested for brain tumor patients. Sleep disturbance and somnolence were frequently reported as the most severely rated symptoms within health-related quality of life across the disease course or treatments, along with fatigue. However, sleep-focused studies yielded inconsistent results in small samples of mostly benign brain tumors in long-term remission from total tumor resection. The research using standardized, multifaceted sleep assessments, particularly in patients with malignant brain tumor and caregivers who are undergoing treatment, is seriously lacking. A more systematic examination of sleep disturbance is warranted to inform the development of better symptom management programs in this population.from Cancer via ola Kala on Inoreader http://ift.tt/2vjpIEH
via IFTTT
Glioblastoma stem cell differentiation into endothelial cells evidenced through live-cell imaging
Abstract
Background.
Glioblastoma cell-initiated vascularization is an alternative angiogenesis called vasculogenic mimicry. However, current knowledge on the mechanism of de novo vessel formation from glioblastoma stem cells (GSCs) is limited. Methods.
Sixty-four glioblastoma samples from patients and 10 fluorescent glioma xenograft samples were examined by immunofluorescence staining for endothelial marker (CD34 and CD31) and glial cell marker (glial fibrillary acidic protein [GFAP]) expression. GSCs were then isolated from human glioblastoma tissue and CD133+/Sox2+ red fluorescent protein-containing (RFP)–GSC-1 cells were established. The ability of these cells to form vascular structures was examined by live-cell imaging of 3D cultures. Results.
CD34-GFAP or CD31-GFAP coexpressing glioblastoma-derived endothelial cells (GDEC) were found in 30 of 64 (46.9%) of clinical glioblastoma samples. In those 30 samples, GDEC were found to form vessel structures in 21 (70%) samples. Among 21 samples with GDEC vessels, the CD34+ GDEC vessels and CD31+ GDEC vessels accounted for about 14.16% and 18.08% of total vessels, respectively. In the xenograft samples, CD34+ GDEC were found in 7 out of 10 mice, and 4 out of 7 mice had CD34+ GDEC vessels. CD31+ GDEC were also found in 7 mice, and 4 mice had CD31+ GDEC vessels (10 mice in total). Through live-cell imaging, we observed gradual CD34 expression when cultured with vascular endothelial growth factor in some glioma cells, and a dynamic increase in endothelial marker expression in RFP–GSC-1 in vitro was recorded. Cells expressed CD34 (9.46%) after 6 hours in culture. Conclusions.
The results demonstrated that GSCs may differentiate into endothelial cells and promote angiogenesis in glioblastomas.from Cancer via ola Kala on Inoreader http://ift.tt/2uJAwib
via IFTTT
A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study
Abstract
Background.
Activation of the mitogen-activated protein kinase pathway is important for growth of pediatric low-grade gliomas (LGGs). The aim of this study was to determine the recommended phase II dose (RP2D) and the dose-limiting toxicities (DLTs) of the MEK inhibitor selumetinib in children with progressive LGG. Methods.
Selumetinib was administered orally starting at 33 mg/m2/dose b.i.d., using the modified continual reassessment method. Pharmacokinetic analysis was performed during the first course. BRAF aberrations in tumor tissue were determined by real-time polymerase chain reaction and fluorescence in situ hybridization. Results.
Thirty-eight eligible subjects were enrolled. Dose levels 1 and 2 (33 and 43 mg/m2/dose b.i.d.) were excessively toxic. DLTs included grade 3 elevated amylase/lipase (n = 1), headache (n = 1), mucositis (n = 2), and grades 2–3 rash (n = 6). At dose level 0 (25 mg/m2/dose b.i.d, the RP2D), only 3 of 24 subjects experienced DLTs (elevated amylase/lipase, rash, and mucositis). At the R2PD, the median (range) area under the curve (AUC0-∞) and apparent oral clearance of selumetinib were 3855 ng*h/mL (1780 to 7250 ng × h/mL) and 6.5 L × h−1 × m−2 (3.4 to 14.0 L × h−1 × m−2), respectively. Thirteen of 19 tumors had BRAF abnormalities. Among the 5 (20%) of 25 subjects with sustained partial responses, all at the RP2D, 4 had BRAF aberrations, 1 had insufficient tissue. Subjects received a median of 13 cycles (range: 1–26). Fourteen (37%) completed all protocol treatment (26 cycles [n = 13], 13 cycles [n = 1]) with at least stable disease; 2-year progression-free survival at the RP2D was 69 ± SE 9.8%. Conclusion.
Selumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs.from Cancer via ola Kala on Inoreader http://ift.tt/2vkldcL
via IFTTT
The transcription factor Olig2 is important for the biology of diffuse intrinsic pontine gliomas
Abstract
Background.
Diffuse intrinsic pontine glioma (DIPG) is a high-grade brainstem glioma of children with dismal prognosis. There is no single unifying model about the cell of origin of DIPGs. Proliferating cells in the developing human and mouse pons, the site of DIPGs, express neural stem/progenitor cell (NPC) markers, including Sox2, nestin, vimentin, Olig2, and glial fibrillary acidic protein, in an overlapping and non-overlapping manner, suggesting progenitor cell heterogeneity in the pons. It is thought that during a restricted window of postnatal pons development, a differentiation block caused by genetic/epigenetic changes leads to unrestrained progenitor proliferation and DIPG development. Nearly 80% of DIPGs harbor a mutation in the H3F3A or the related HIST1H3B gene. Supporting the impaired differentiation model, NPCs derived from human induced pluripotent stem cells expressing the H3F3A mutation showed complete differentiation block. However, the mechanisms regulating an altered differentiation program in DIPG are unknown. Methods.
We established syngeneic serum-dependent and independent primary DIPG lines, performed molecular characterization of DIPG lines in vitro and in an orthotopic xenograft model, and used small hairpin RNA to examine Olig2 function in DIPG. Results.
The transcription factor Olig2 is highly expressed in 70%–80% of DIPGs. Here we report that Olig2 expression and DIPG differentiation are mutually exclusive events in vitro, and only DIPG cells that retained Olig2 in vitro formed robust Olig2-positive brainstem glioma with 100% penetrance in a xenograft model. Conclusion.
Our results indicate Olig2 as an onco-requisite factor in DIPG and propose investigation of Olig2 target genes as novel candidates in DIPG therapy.from Cancer via ola Kala on Inoreader http://ift.tt/2uJwmai
via IFTTT
The clinical value of patient-derived glioblastoma tumorspheres in predicting treatment response
Abstract
Background.
Advances from glioma stemlike cell (GSC) research, though increasing our knowledge of glioblastoma (GBM) biology, do not influence clinical decisions yet. We explored the translational power of GSC-enriched cultures from patient-derived tumorspheres (TS) in predicting treatment response. Methods.
The relationship between TS growth and clinical outcome was investigated in 52 GBMs treated with surgical resection followed by radiotherapy and temozolomide (TMZ). The effect on TS of radiation (6 to 60 Gy) and of TMZ (3.9 μM to 1 mM) was related with patients' survival. Results.
Generation of TS was an independent factor for poor overall survival (OS) and poor progression-free survival (PFS) (P < .0001 and P = .0010, respectively). Growth rate and clonogenicity of TS predicted poor OS. In general, TS were highly resistant to both radiation and TMZ. Resistance to TMZ was stronger in TS with high clonogenicity and fast growth (P < .02). Shorter PFS was associated with radiation LD50 (lethal dose required to kill 50% of TS cells) >12 Gy of matched TS (P = .0484). A direct relationship was found between sensitivity of TS to TMZ and patients' survival (P = .0167 and P = .0436 for OS and PFS, respectively). Importantly, values for TMZ half-maximal inhibitory concentration <50 μM, which are in the range of plasma levels achieved in vivo, identified cases with longer OS and PFS (P = .0020 and P = .0016, respectively). Conclusions.
Analysis of TS holds translational relevance by predicting the response of parent tumors to radiation and, particularly, to TMZ. Dissecting the clonogenic population from proliferating progeny in TS can guide therapeutic strategies to a more effective drug selection and treatment duration.from Cancer via ola Kala on Inoreader http://ift.tt/2vk8qHd
via IFTTT
Evaluating the significance of density, localization, and PD-1/PD-L1 immunopositivity of mononuclear cells in the clinical course of lung adenocarcinoma patients with brain metastasis
Abstract
Background.
Management of lung cancer patients who suffer from brain metastases represents a major challenge. Considering the promising results with immune checkpoint inhibitor treatment, evaluating the status of immune cell (IC) infiltrates in the prognosis of brain metastasis may lead to better therapeutic strategies with these agents. The aim of this study was to characterize the distribution of ICs and determine the expression of the checkpoint molecules programmed death protein 1 (PD-1) and its ligand, PD-L1, in brain metastasis of lung adenocarcinoma (LUAD) patients and to analyze their clinicopathological correlations. Methods.
We determined the presence of peritumoral mononuclear cells (mononuclear ring) and the density of intratumoral stromal mononuclear cells on brain metastasis tissue sections of 208 LUAD patients. PD-L1/PD-1 expressions were analyzed by immunohistochemistry. Results.
Mononuclear rings were significantly associated with better survival after brain metastasis surgery. Cases with massive stromal IC infiltration also showed a tendency for better overall survival. Lower expression of PD-1 and PD-L1 was associated with better survival in patients who underwent surgery for the primary tumor and had multiple brain metastases. Steroid administration and chemotherapy appear not to influence the density of IC in brain metastasis. Conclusion.
This is the first study demonstrating the independent prognostic value of mononuclear rings in LUAD cases with brain metastasis. Our results also suggest that the density of tumor-associated ICs in addition to PD-L1 expression of tumor cells and ICs as well as PD-1 expression of ICs may hold relevant information for the appropriate selection of patients who might benefit from anti–PD-L1 or anti–PD-1 therapy.from Cancer via ola Kala on Inoreader http://ift.tt/2uJAtD1
via IFTTT
Εγγραφή σε:
Αναρτήσεις (Atom)