Publication date: June 2017
Source:Cancer Epidemiology, Volume 48
Author(s): Minjoung Monica Koo, Christian von Wagner, Gary A. Abel, Sean McPhail, Greg P. Rubin, Georgios Lyratzopoulos
IntroductionMost symptomatic women with breast cancer have relatively short diagnostic intervals but a substantial minority experience prolonged journeys to diagnosis. Atypical presentations (with symptoms other than breast lump) may be responsible.MethodsWe examined the presenting symptoms of breast cancer in women using data from a national audit initiative (n=2316). Symptoms were categorised topographically. We investigated variation in the length of the patient interval (time from symptom onset to presentation) and the primary care interval (time from presentation to specialist referral) across symptom groups using descriptive analyses and quantile regression.ResultsA total of 56 presenting symptoms were described: breast lump was the most frequent (83%) followed by non-lump breast symptoms, (e.g. nipple abnormalities (7%) and breast pain (6%)); and non-breast symptoms (e.g. back pain (1%) and weight loss (0.3%)).Greater proportions of women with 'non-lump only' and 'both lump and non-lump' symptoms waited 90days or longer before seeking help compared to those with 'breast lump only' (15% and 20% vs. 7% respectively). Quantile regression indicated that the differences in the patient interval persisted after adjusting for age and ethnicity, but there was little variation in primary care interval for the majority of women.ConclusionsAbout 1 in 6 women with breast cancer present with a large spectrum of symptoms other than breast lump. Women who present with non-lump breast symptoms tend to delay seeking help. Further emphasis of breast symptoms other than breast lump in symptom awareness campaigns is warranted.
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Τρίτη 23 Μαΐου 2017
Typical and atypical presenting symptoms of breast cancer and their associations with diagnostic intervals: Evidence from a national audit of cancer diagnosis
Involvement of the DNA mismatch repair system in cisplatin sensitivity of testicular germ cell tumours
Abstract
Background
Testicular germ cell tumours (TGCT) are highly sensitive to cisplatin-based chemotherapy, but patients with tumours containing differentiated teratoma components are less responsive to this treatment. The cisplatin sensitivity in TGCT has previously been linked to the embryonic phenotype in the majority of tumours, although the underlying mechanism largely remains to be elucidated. The aim of this study was to investigate the role of the DNA mismatch repair (MMR) system in the cisplatin sensitivity of TGCT.
Methods
The expression pattern of key MMR proteins, including MSH2, MSH6, MLH1 and PMS2, were investigated during testis development and in the pathogenesis of TGCT, including germ cell neoplasia in situ (GCNIS). The TGCT-derived cell line NTera2 was differentiated using retinoic acid (10 μM, 6 days) after which MMR protein expression and activity, as well as cisplatin sensitivity, were investigated in both undifferentiated and differentiated cells. Finally, the expression of MSH2 was knocked down by siRNA in NTera2 cells after which the effect on cisplatin sensitivity was examined.
Results
MMR proteins were expressed in proliferating cells in the testes, while in malignant germ cells MMR protein expression was found to coincide with the expression of the pluripotency factor OCT4, with no or low expression in the more differentiated yolk sac tumours, choriocarcinomas and teratomas. In differentiated NTera2 cells we found a significantly (p < 0.05) lower expression of the MMR and pluripotency factors, as well as a reduced MMR activity and cisplatin sensitivity, compared to undifferentiated NTera2 cells. Also, we found that partial knockdown of MSH2 expression in undifferentiated NTera2 cells resulted in a significantly (p < 0.001) reduced cisplatin sensitivity.
Conclusion
This study reports, for the first time, expression of the MMR system in fetal gonocytes, from which GCNIS cells are derived. Our findings in primary TGCT specimens and TGCT-derived cells suggest that a reduced sensitivity to cisplatin in differentiated TGCT components could result from a reduced expression of MMR proteins, in particular MSH2 and MLH1, which are involved in the recognition of cisplatin adducts and in activation of the DNA damage response pathway to initiate apoptosis.
http://ift.tt/2rQUodY
Involvement of the DNA mismatch repair system in cisplatin sensitivity of testicular germ cell tumours
Abstract
Background
Testicular germ cell tumours (TGCT) are highly sensitive to cisplatin-based chemotherapy, but patients with tumours containing differentiated teratoma components are less responsive to this treatment. The cisplatin sensitivity in TGCT has previously been linked to the embryonic phenotype in the majority of tumours, although the underlying mechanism largely remains to be elucidated. The aim of this study was to investigate the role of the DNA mismatch repair (MMR) system in the cisplatin sensitivity of TGCT.
Methods
The expression pattern of key MMR proteins, including MSH2, MSH6, MLH1 and PMS2, were investigated during testis development and in the pathogenesis of TGCT, including germ cell neoplasia in situ (GCNIS). The TGCT-derived cell line NTera2 was differentiated using retinoic acid (10 μM, 6 days) after which MMR protein expression and activity, as well as cisplatin sensitivity, were investigated in both undifferentiated and differentiated cells. Finally, the expression of MSH2 was knocked down by siRNA in NTera2 cells after which the effect on cisplatin sensitivity was examined.
Results
MMR proteins were expressed in proliferating cells in the testes, while in malignant germ cells MMR protein expression was found to coincide with the expression of the pluripotency factor OCT4, with no or low expression in the more differentiated yolk sac tumours, choriocarcinomas and teratomas. In differentiated NTera2 cells we found a significantly (p < 0.05) lower expression of the MMR and pluripotency factors, as well as a reduced MMR activity and cisplatin sensitivity, compared to undifferentiated NTera2 cells. Also, we found that partial knockdown of MSH2 expression in undifferentiated NTera2 cells resulted in a significantly (p < 0.001) reduced cisplatin sensitivity.
Conclusion
This study reports, for the first time, expression of the MMR system in fetal gonocytes, from which GCNIS cells are derived. Our findings in primary TGCT specimens and TGCT-derived cells suggest that a reduced sensitivity to cisplatin in differentiated TGCT components could result from a reduced expression of MMR proteins, in particular MSH2 and MLH1, which are involved in the recognition of cisplatin adducts and in activation of the DNA damage response pathway to initiate apoptosis.
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Airway management during induction of anaesthesia, spontaneous ventilation (SV) and controlled mechanical ventilation (CMV), using an endotracheal tube (ETT), laryngeal mask (LM), rabbit-specific supraglottic airway device (v-gel) or facemask (FM).
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
Curcumin attenuates lipopolysaccharide/d-galactosamine-induced acute liver injury
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
Randomized Phase 3 Trial of Ombitasvir/Paritaprevir/Ritonavir and Ribavirin for Hepatitis C Virus Genotype 2-Infected Japanese Patients
Abstract
Introduction
In Japan, hepatitis C virus (HCV) genotype (GT) 2 accounts for approximately 32% of HCV infections. Limited treatment options exist in Japan for HCV GT2-infected patients. GIFT-II was a phase 3, randomized, open-label study evaluating the efficacy and safety of 16- and 12-week regimens of co-formulated ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) plus ribavirin (RBV) in Japanese adults with HCV GT2 infection.
Methods
Patients were randomized in a 1:1 ratio to once-daily, co-formulated OBV/PTV/r (25/150/100 mg) with weight-based RBV for 16 or 12 weeks. The primary efficacy endpoint was the sustained virologic response at 12 weeks post-treatment (SVR12) rate in the primary efficacy population of non-cirrhotic treatment-naive patients.
Results
A total of 171 patients were randomized to OBV/PTV/r + RBV. In the primary efficacy population, SVR12 rates were 91.5% (43/47; 95% confidence interval 83.5–99.5%) and 75.0% (36/48; 95% confidence interval 62.8–87.2%) in the 16-week arm and 12-week arm, respectively. No patient in the 16-week arm relapsed by post-treatment week 12. Among non-cirrhotic treatment-experienced patients, the overall SVR rate in the 16-week arm was 75.8% (25/33) and was highest [93.8% (15/16)] among those who had relapsed after previous interferon-based therapy. SVR12 rates were consistently higher in patients with HCV GT2a infection versus HCV GT2b infection [16-week treatment arm: 93.9% (31/33) versus 85.7% (12/14) and 93.8% (15/16) versus 56.3% (9/16) among non-cirrhotic treatment-naive and treatment-experienced patients, respectively]. No patient discontinued treatment because of an adverse event. The most common adverse events were anemia, increased blood bilirubin, and nasopharyngitis.
Conclusions
OBV/PTV/r + RBV for 16 weeks resulted in high SVR12 rates in non-cirrhotic Japanese patients infected with HCV GT2 who were treatment-naive or who had relapsed after an interferon-based therapy. Higher SVR12 rates were observed among patients with HCV GT2a infection versus those with GT2b infection. This regimen demonstrated a favorable safety profile.
Trial Registration: ClinicalTrials.gov identifier, NCT02023112.
Funding: AbbVie.
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Study Design of VESUTO ® : Efficacy of Tiotropium/Olodaterol on Lung Hyperinflation, Exercise Capacity, and Physical Activity in Japanese Patients with Chronic Obstructive Pulmonary Disease
Abstract
Introduction
The superiority of tiotropium/olodaterol is demonstrated in improvement of lung function, dyspnea, lung hyperinflation, and quality of life compared with either monotherapy in patients with chronic obstructive pulmonary disease (COPD). Japanese Respiratory Society Guidelines for COPD management include improvement of exercise tolerance and daily physical activity as the treatment goals; however, there is limited evidence in Japanese patients with COPD.
Methods
A protocol is developed for the VESUTO® study that investigates the efficacy of tiotropium/olodaterol fixed-dose combination (FDC) compared with tiotropium alone on inspiratory capacity (IC, volume from functional residual capacity to total lung capacity), exercise capacity, and daily physical activity in Japanese patients with COPD.
Results
A total of 180 Japanese patients with COPD, aged ≥40 years will be enrolled into the double-blind, multicenter, active-controlled, crossover study (NCT02629965) and will be randomized to receive either tiotropium/olodaterol FDC or tiotropium for 6 weeks each [two puffs via RESPIMAT® (Boehringer Ingelheim, Ingelheim, Germany) inhaler in the morning]. The primary endpoint is IC at rest measured at 60 min post-dose after 6 weeks treatment. The secondary endpoints include the 6-min walk distance (6MWD) at 90 min post-dose and physical activity measured by the activity monitor in the last 2 weeks of the 6-week treatment periods. Lung function tests will also be assessed after 6 weeks treatment. A mixed-effects model repeated measures approach will be used for the primary and secondary endpoints.
Conclusion
The VESUTO® study is the first randomized interventional study to investigate exercise capacity (6MWD) and physical activity measured by a 3-axis accelerometer in Japanese patients with COPD. The study could provide additional evidence of long-acting muscarinic antagonist (LAMA) + long-acting β2-agonist (LABA) combination therapy on patients' physical activities as well as lung function.
Trial registration
ClinicalTrials.gov: NCT02629965 (registered on December 1, 2015).
Funding
The VESUTO study was funded by Nippon Boehringer Ingelheim Co., Ltd., Tokyo, Japan.
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Life Impact and Treatment Preferences of Individuals with Asthma and Chronic Obstructive Pulmonary Disease: Results from Qualitative Interviews and Focus Groups
Abstract
Introduction
The impact of asthma and chronic obstructive pulmonary disease (COPD) on individuals' lives may be substantial, yet clinical practice often focuses only on symptoms. We aimed to better understand the perspective of asthma or COPD patients and to identify condition-related burden, life impact, priorities, unmet needs, and treatment goals.
Methods
Individuals aged at least 18 years with asthma or COPD were identified by a recruitment panel via clinical referrals, support groups, consumer networks, and a patient database. Interviews were carried out individually (by telephone) or in focus groups (with no more than five participants per group). A semi-structured interview guide was used with prespecified topics, informed by a literature review, that were considered impactful in asthma or COPD (symptoms and daily-life impact, satisfaction with current treatment, important aspects of treatment, adherence, and ideal treatment).
Results
Overall, 72 people participated in focus groups/individual interviews (asthma n = 18/n = 21; COPD n = 15/n = 18). "Shortness of breath" was the most frequently reported symptom; however, participants discussed the life impact of their condition more than symptoms alone. Reported physical impacts included the inability to sleep and socialize, while emotional impacts included "embarrassment, stigma, and/or self-consciousness", "fear and/or panic", and "sadness, anxiety, and/or depression". Coping mechanisms for normal activities included continuing at reduced pace and avoidance. Treatment preferences centered on resolving impacts; improved sleep, "speed of action", and "length of relief" were the most frequently reported ideal treatment factors.
Conclusion
Patients with asthma or COPD experience substantial quality of life limitations and tend to focus on these in their expressions of concern, rather than symptoms per se. Life impacts of these conditions may have implications beyond those commonly appreciated in routine practice; these considerations will be applied to a future discrete choice experiment survey.
Funding
GSK funded study (H0-15-15502/204821).
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Advances in Clinical Cardiology 2016: A Summary of the Key Clinical Trials
Abstract
Introduction
The findings of many new cardiology clinical trials over the last year have been published or presented at major international meetings. This paper aims to describe and place in context a summary of the key clinical trials in cardiology presented between January and December 2016.
Methods
The authors reviewed clinical trials presented at major cardiology conferences during 2016 including the American College of Cardiology (ACC), European Association for Percutaneous Cardiovascular Interventions (EuroPCR), European Society of Cardiology (ESC), European Association for the Study of Diabetes (EASD), Transcatheter Cardiovascular Therapeutics (TCT), and the American Heart Association (AHA). Selection criteria were trials with a broad relevance to the cardiology community and those with potential to change current practice.
Results
A total of 57 key cardiology clinical trials were identified for inclusion. Here we describe and place in clinical context the key findings of new data relating to interventional and structural cardiology including delayed stenting following primary angioplasty, contrast-induced nephropathy, management of jailed wires, optimal duration of dual antiplatelet therapy (DAPT), stenting vs bypass for left main disease, new generation stents (BioFreedom, Orsiro, Absorb), transcatheter aortic valve implantation (Edwards Sapien XT, transcatheter embolic protection), and closure devices (Watchman, Amplatzer). New preventative cardiology data include trials of bariatric surgery, empagliflozin, liraglutide, semaglutide, PCSK9 inhibitors (evolocumab and alirocumab), and inclisiran. Antiplatelet therapy trials include platelet function monitoring and ticagrelor vs clopidogrel for peripheral vascular disease. New data are also presented in fields of heart failure (sacubitril/valsartan, aliskiren, spironolactone), atrial fibrillation (rivaroxaban in patients undergoing coronary intervention, edoxaban in DC cardioversion), cardiac devices (implantable cardioverter defibrillator in non-ischemic cardiomyopathy), and electrophysiology (cryoballoon vs radiofrequency ablation).
Conclusion
This paper presents a summary of key clinical cardiology trials during the past year and should be of practical value to both clinicians and cardiology researchers.
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Study Design of VESUTO ® : Efficacy of Tiotropium/Olodaterol on Lung Hyperinflation, Exercise Capacity, and Physical Activity in Japanese Patients with Chronic Obstructive Pulmonary Disease
Abstract
Introduction
The superiority of tiotropium/olodaterol is demonstrated in improvement of lung function, dyspnea, lung hyperinflation, and quality of life compared with either monotherapy in patients with chronic obstructive pulmonary disease (COPD). Japanese Respiratory Society Guidelines for COPD management include improvement of exercise tolerance and daily physical activity as the treatment goals; however, there is limited evidence in Japanese patients with COPD.
Methods
A protocol is developed for the VESUTO® study that investigates the efficacy of tiotropium/olodaterol fixed-dose combination (FDC) compared with tiotropium alone on inspiratory capacity (IC, volume from functional residual capacity to total lung capacity), exercise capacity, and daily physical activity in Japanese patients with COPD.
Results
A total of 180 Japanese patients with COPD, aged ≥40 years will be enrolled into the double-blind, multicenter, active-controlled, crossover study (NCT02629965) and will be randomized to receive either tiotropium/olodaterol FDC or tiotropium for 6 weeks each [two puffs via RESPIMAT® (Boehringer Ingelheim, Ingelheim, Germany) inhaler in the morning]. The primary endpoint is IC at rest measured at 60 min post-dose after 6 weeks treatment. The secondary endpoints include the 6-min walk distance (6MWD) at 90 min post-dose and physical activity measured by the activity monitor in the last 2 weeks of the 6-week treatment periods. Lung function tests will also be assessed after 6 weeks treatment. A mixed-effects model repeated measures approach will be used for the primary and secondary endpoints.
Conclusion
The VESUTO® study is the first randomized interventional study to investigate exercise capacity (6MWD) and physical activity measured by a 3-axis accelerometer in Japanese patients with COPD. The study could provide additional evidence of long-acting muscarinic antagonist (LAMA) + long-acting β2-agonist (LABA) combination therapy on patients' physical activities as well as lung function.
Trial registration
ClinicalTrials.gov: NCT02629965 (registered on December 1, 2015).
Funding
The VESUTO study was funded by Nippon Boehringer Ingelheim Co., Ltd., Tokyo, Japan.
http://ift.tt/2qgXKpe
Randomized Phase 3 Trial of Ombitasvir/Paritaprevir/Ritonavir and Ribavirin for Hepatitis C Virus Genotype 2-Infected Japanese Patients
Abstract
Introduction
In Japan, hepatitis C virus (HCV) genotype (GT) 2 accounts for approximately 32% of HCV infections. Limited treatment options exist in Japan for HCV GT2-infected patients. GIFT-II was a phase 3, randomized, open-label study evaluating the efficacy and safety of 16- and 12-week regimens of co-formulated ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) plus ribavirin (RBV) in Japanese adults with HCV GT2 infection.
Methods
Patients were randomized in a 1:1 ratio to once-daily, co-formulated OBV/PTV/r (25/150/100 mg) with weight-based RBV for 16 or 12 weeks. The primary efficacy endpoint was the sustained virologic response at 12 weeks post-treatment (SVR12) rate in the primary efficacy population of non-cirrhotic treatment-naive patients.
Results
A total of 171 patients were randomized to OBV/PTV/r + RBV. In the primary efficacy population, SVR12 rates were 91.5% (43/47; 95% confidence interval 83.5–99.5%) and 75.0% (36/48; 95% confidence interval 62.8–87.2%) in the 16-week arm and 12-week arm, respectively. No patient in the 16-week arm relapsed by post-treatment week 12. Among non-cirrhotic treatment-experienced patients, the overall SVR rate in the 16-week arm was 75.8% (25/33) and was highest [93.8% (15/16)] among those who had relapsed after previous interferon-based therapy. SVR12 rates were consistently higher in patients with HCV GT2a infection versus HCV GT2b infection [16-week treatment arm: 93.9% (31/33) versus 85.7% (12/14) and 93.8% (15/16) versus 56.3% (9/16) among non-cirrhotic treatment-naive and treatment-experienced patients, respectively]. No patient discontinued treatment because of an adverse event. The most common adverse events were anemia, increased blood bilirubin, and nasopharyngitis.
Conclusions
OBV/PTV/r + RBV for 16 weeks resulted in high SVR12 rates in non-cirrhotic Japanese patients infected with HCV GT2 who were treatment-naive or who had relapsed after an interferon-based therapy. Higher SVR12 rates were observed among patients with HCV GT2a infection versus those with GT2b infection. This regimen demonstrated a favorable safety profile.
Trial Registration: ClinicalTrials.gov identifier, NCT02023112.
Funding: AbbVie.
http://ift.tt/2qLVLNm
Life Impact and Treatment Preferences of Individuals with Asthma and Chronic Obstructive Pulmonary Disease: Results from Qualitative Interviews and Focus Groups
Abstract
Introduction
The impact of asthma and chronic obstructive pulmonary disease (COPD) on individuals' lives may be substantial, yet clinical practice often focuses only on symptoms. We aimed to better understand the perspective of asthma or COPD patients and to identify condition-related burden, life impact, priorities, unmet needs, and treatment goals.
Methods
Individuals aged at least 18 years with asthma or COPD were identified by a recruitment panel via clinical referrals, support groups, consumer networks, and a patient database. Interviews were carried out individually (by telephone) or in focus groups (with no more than five participants per group). A semi-structured interview guide was used with prespecified topics, informed by a literature review, that were considered impactful in asthma or COPD (symptoms and daily-life impact, satisfaction with current treatment, important aspects of treatment, adherence, and ideal treatment).
Results
Overall, 72 people participated in focus groups/individual interviews (asthma n = 18/n = 21; COPD n = 15/n = 18). "Shortness of breath" was the most frequently reported symptom; however, participants discussed the life impact of their condition more than symptoms alone. Reported physical impacts included the inability to sleep and socialize, while emotional impacts included "embarrassment, stigma, and/or self-consciousness", "fear and/or panic", and "sadness, anxiety, and/or depression". Coping mechanisms for normal activities included continuing at reduced pace and avoidance. Treatment preferences centered on resolving impacts; improved sleep, "speed of action", and "length of relief" were the most frequently reported ideal treatment factors.
Conclusion
Patients with asthma or COPD experience substantial quality of life limitations and tend to focus on these in their expressions of concern, rather than symptoms per se. Life impacts of these conditions may have implications beyond those commonly appreciated in routine practice; these considerations will be applied to a future discrete choice experiment survey.
Funding
GSK funded study (H0-15-15502/204821).
http://ift.tt/2qM5q6j
Advances in Clinical Cardiology 2016: A Summary of the Key Clinical Trials
Abstract
Introduction
The findings of many new cardiology clinical trials over the last year have been published or presented at major international meetings. This paper aims to describe and place in context a summary of the key clinical trials in cardiology presented between January and December 2016.
Methods
The authors reviewed clinical trials presented at major cardiology conferences during 2016 including the American College of Cardiology (ACC), European Association for Percutaneous Cardiovascular Interventions (EuroPCR), European Society of Cardiology (ESC), European Association for the Study of Diabetes (EASD), Transcatheter Cardiovascular Therapeutics (TCT), and the American Heart Association (AHA). Selection criteria were trials with a broad relevance to the cardiology community and those with potential to change current practice.
Results
A total of 57 key cardiology clinical trials were identified for inclusion. Here we describe and place in clinical context the key findings of new data relating to interventional and structural cardiology including delayed stenting following primary angioplasty, contrast-induced nephropathy, management of jailed wires, optimal duration of dual antiplatelet therapy (DAPT), stenting vs bypass for left main disease, new generation stents (BioFreedom, Orsiro, Absorb), transcatheter aortic valve implantation (Edwards Sapien XT, transcatheter embolic protection), and closure devices (Watchman, Amplatzer). New preventative cardiology data include trials of bariatric surgery, empagliflozin, liraglutide, semaglutide, PCSK9 inhibitors (evolocumab and alirocumab), and inclisiran. Antiplatelet therapy trials include platelet function monitoring and ticagrelor vs clopidogrel for peripheral vascular disease. New data are also presented in fields of heart failure (sacubitril/valsartan, aliskiren, spironolactone), atrial fibrillation (rivaroxaban in patients undergoing coronary intervention, edoxaban in DC cardioversion), cardiac devices (implantable cardioverter defibrillator in non-ischemic cardiomyopathy), and electrophysiology (cryoballoon vs radiofrequency ablation).
Conclusion
This paper presents a summary of key clinical cardiology trials during the past year and should be of practical value to both clinicians and cardiology researchers.
http://ift.tt/2qgIJ6W
Gene Expression Profiling in BRAF-Mutated Melanoma Reveals Patient Subgroups With Poor Outcomes to Vemurafenib That May Be Overcome by Cobimetinib Plus Vemurafenib
Purpose: The association of tumor gene expression profiles with progression-free survival (PFS) outcomes in patients with BRAFV600-mutated melanoma treated with vemurafenib or cobimetinib combined with vemurafenib was evaluated. <br /><br />Experimental Design: Gene expression of archival tumor samples from patients in four trials (BRIM-2, BRIM-3, BRIM-7, and coBRIM) was evaluated. Genes significantly associated with PFS (P<0 .05) were identified by univariate Cox proportional hazards modeling, then subjected to unsupervised hierarchical clustering, principal component analysis, and recursive partitioning to develop optimized gene signatures.<br /><br />Results: <p>Forty-six genes were identified as significantly associated with PFS in both BRIM-2 (n = 63) and the vemurafenib arm of BRIM-3 (n = 160). Two distinct signatures were identified: cell cycle and immune. Among vemurafenib-treated patients, the cell cycle signature was associated with shortened PFS compared with the immune signature in the BRIM-2/BRIM-3 training set (hazard ratio [HR] 1.8, 95% confidence interval [CI], 1.3-2.6, P = 0.0001) and in the coBRIM validation set (n = 101; HR 1.6, 95% CI, 1.0-2.5, P = 0.08). The adverse impact of the cell cycle signature on PFS was not observed in patients treated with cobimetinib combined with vemurafenib (n = 99; HR 1.1, 95% CI, 0.7-1.8, P = 0.66).</p> Conclusions: In vemurafenib-treated patients, the cell cycle gene signature was associated with shorter PFS. However, in cobimetinib combined with vemurafenib-treated patients, both cell cycle and immune signature subgroups had comparable PFS. Cobimetinib combined with vemurafenib may abrogate the adverse impact of the cell cycle signature.
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Shaping the tumor stroma and sparking immune activation by CD40 and 4-1BB signaling induced by an armed oncolytic virus
Purpose: Pancreatic cancer is a severe indication with short expected survival despite surgery and/or combination chemotherapeutics. Checkpoint blockade antibodies are approved for several cancer indications but pancreatic cancer has remained refractory. However, there are clinical data suggesting that stimulation of the CD40 pathway may be of interest for these patients. Oncolytic viruses armed with immunostimulatory genes represent an interesting approach. Herein we present LOAd703, a designed adenovirus armed with trimerized CD40L and 4-1BBL that activate the CD40 and 4-1BB pathways, respectively. Since many cells in the tumor stroma, including stellate cells, and the infiltrating immune cells express CD40 and some 4-1BB, we hypothesize that LOAd703 activates immunity and simultaneously modulates the biology of the tumor stroma. <p>Experimental design: Tumor-, stellate-, endothelial-, and immune cells were infected by LOAd703 and investigated by flow cytometry, proteomics and functional analyses.</p> <p>Results: LOAd703-infected pancreatic cell lines were killed by oncolysis and the virus was more effective than standard of care gemcitabine. In in vivo xenograft models, LOAd703 efficiently reduced established tumors and could be combined with gemcitabine for additional effect. Infected stellate- and tumor cells reduced factors that promote tumor growth (Spp-1, Gal-3, HGF, TGF-beta and collagen type I), while chemokines were increased. Molecules involved in lymphocyte migration were upregulated on infected endothelial cells. Dendritic cells were robustly stimulated by LOAd703 to produce co-stimulators, cytokines and chemokines, and such DCs potently expanded both antigen-specific T cells and NK cells. Conclusions: LOAd703 is a potent immune activator that modulates the stroma to support antitumor responses.
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Immune correlates of GM-CSF and melanoma peptide vaccination in a randomized trial for the adjuvant therapy of resected high-risk melanoma (E4697)
Purpose: E4697 was a multi-center intergroup randomized placebo-controlled Phase III trial of adjuvant GM-CSF and/or a multi-epitope melanoma peptide vaccine for patients with completely resected, high-risk stage III/IV melanoma. <p>Experimental Design: 815 patients were enrolled from 12/99 to 10/06 into this 6-arm study. GM-CSF was chosen to promote the numbers and functions of dendritic cells (DC). The melanoma antigen peptide vaccine (Tyrosinase368-376 (370D), gp100209-217 (210M), MART-127-35) in Montanide was designed to promote melanoma specific CD8+ T cell responses.</p> <p>Results: Although the overall RFS and OS were not significantly improved with the vaccine or GM-CSF when compared with placebo, immunomodulatory effects were observed in peripheral blood and served as important correlates to this therapeutic study. Peripheral blood was examined to evaluate the impact of GM-CSF and/or the peptide vaccine on peripheral blood immunity and to investigate potential predictive or prognostic biomarkers. 11.3% of unvaccinated patients and 27.1% of vaccinated patients developed peptide-specific CD8+ T cell responses. HLA-A2+ patients who had any peptide-specific CD8+ T cell response at day +43 tended to have poorer OS in univariate analysis. Patients receiving GM-CSF had significant reduction in percentages of circulating myeloid dendritic cells (mDC) and plasmacytoid DC (pDC) at day +43. In a subset of patients who received GM-CSF, circulating myeloid-derived suppressor cells (MDSC), and anti-GM-CSF neutralizing antibodies (Nabs) were also modulated. The majority of patients developed anti-GM-CSF Nabs, which correlated with improved RFS and OS.</p> Conclusions: The assessment of cellular and humoral responses identified counter-intuitive immune system changes correlating with clinical outcome.
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CHRONIC LYMPHOCYTIC LEUKEMIA WITH MUTATED IGHV4-34 RECEPTORS: SHARED AND DISTINCT IMMUNOGENETIC FEATURES AND CLINICAL OUTCOMES
Purpose:We sought to investigate if B cell receptor immunoglobulin (BcR IG) stereotypy is associated with particular clinicobiological features amongst chronic lymphocytic leukemia (CLL) patients expressing mutated BcR IG (M-CLL) encoded by the IGHV4-34 gene, and also ascertain whether these associations could refine prognostication.<br /> <p>Experimental Design: In a series of 19,907 CLL cases with available immunogenetic information, we identified 339 IGHV4-34 expressing cases assigned to one of the four largest stereotyped M-CLL subsets, namely subsets #4, #16, #29 and #201, and investigated in detail their clinicobiological characteristics and disease outcomes.</p> Results:We identified shared and subset-specific patterns of somatic hypermutation (SHM) amongst patients assigned to these subsets. The greatest similarity was observed between subsets #4 and #16, both including IgG-switched cases (IgG-CLL). In contrast, the least similarity was detected between subsets #16 and #201, the latter concerning IgM/D-expressing CLLs. Significant differences between subsets also involved disease stage at diagnosis and the presence of specific genomic aberrations. IgG subsets #4 and #16 emerged as particularly indolent with a significantly (p<0.05) longer time-to-first-treatment (TTFT) (median TTFT: not yet reached) compared to the IgM/D subsets #29 and #201 (median TTFT: 11 and 12 years, respectively).<br /><br />Conclusions:Our findings support the notion that BcR IG stereotypy further refines prognostication in CLL, superseding the immunogenetic distinction based solely on SHM load. Additionally, the observed distinct genetic aberration landscapes and clinical heterogeneity suggests that not all M-CLL cases are equal, prompting further research into the underlying biological background with the ultimate aim of tailored patient management.
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Development and validation of an ultra-deep next-generation sequencing assay for testing of plasma cell-free DNA from patients with advanced cancer
Purpose: Tumor-derived cell-free DNA (cfDNA) in plasma can be used for molecular testing and provide an attractive alternative to tumor tissue. Commonly used PCR-based technologies can test for limited number of alterations at the time. Therefore, novel ultrasensitive technologies capable of testing for a broad spectrum of molecular alterations are needed to further personalized cancer therapy. <p>Experimental Design: We developed a highly sensitive ultra-deep next-generation sequencing (NGS) assay using reagents from TruSeqNano library preparation and NexteraRapid Capture target enrichment kits to generate plasma cfDNA sequencing libraries for mutational analysis in 61 cancer-related genes using common bioinformatics tools. The results were retrospectively compared to molecular testing of archival primary or metastatic tumor tissue obtained at different points of clinical care.</p> <p>Results: In a study of 55 patients with advanced cancer, the ultra-deep NGS assay detected 82% (complete detection) to 87% (complete and partial detection) of the aberrations identified in discordantly collected corresponding archival tumor tissue. Patients with a low variant allele frequency (VAF) of mutant cfDNA survived longer than those with a high VAF did (P=0.018). In patients undergoing systemic therapy, radiological response was positively associated with changes in cfDNA VAF (P=0.02), and compared with unchanged/increased mutant cfDNA VAF, decreased cfDNA VAF was associated with longer time to treatment failure (TTF; P=0.03).</p> <p>Conclusions: Ultra-deep NGS assay has good sensitivity compared to conventional clinical mutation testing of archival specimens. A high VAF in mutant cfDNA corresponded with shorter survival. Changes in VAF of mutated cfDNA were associated with TTF.
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Gene Expression Profiling in BRAF-Mutated Melanoma Reveals Patient Subgroups With Poor Outcomes to Vemurafenib That May Be Overcome by Cobimetinib Plus Vemurafenib
Purpose: The association of tumor gene expression profiles with progression-free survival (PFS) outcomes in patients with BRAFV600-mutated melanoma treated with vemurafenib or cobimetinib combined with vemurafenib was evaluated. <br /><br />Experimental Design: Gene expression of archival tumor samples from patients in four trials (BRIM-2, BRIM-3, BRIM-7, and coBRIM) was evaluated. Genes significantly associated with PFS (P<0 .05) were identified by univariate Cox proportional hazards modeling, then subjected to unsupervised hierarchical clustering, principal component analysis, and recursive partitioning to develop optimized gene signatures.<br /><br />Results: <p>Forty-six genes were identified as significantly associated with PFS in both BRIM-2 (n = 63) and the vemurafenib arm of BRIM-3 (n = 160). Two distinct signatures were identified: cell cycle and immune. Among vemurafenib-treated patients, the cell cycle signature was associated with shortened PFS compared with the immune signature in the BRIM-2/BRIM-3 training set (hazard ratio [HR] 1.8, 95% confidence interval [CI], 1.3-2.6, P = 0.0001) and in the coBRIM validation set (n = 101; HR 1.6, 95% CI, 1.0-2.5, P = 0.08). The adverse impact of the cell cycle signature on PFS was not observed in patients treated with cobimetinib combined with vemurafenib (n = 99; HR 1.1, 95% CI, 0.7-1.8, P = 0.66).</p> Conclusions: In vemurafenib-treated patients, the cell cycle gene signature was associated with shorter PFS. However, in cobimetinib combined with vemurafenib-treated patients, both cell cycle and immune signature subgroups had comparable PFS. Cobimetinib combined with vemurafenib may abrogate the adverse impact of the cell cycle signature.
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Shaping the tumor stroma and sparking immune activation by CD40 and 4-1BB signaling induced by an armed oncolytic virus
Purpose: Pancreatic cancer is a severe indication with short expected survival despite surgery and/or combination chemotherapeutics. Checkpoint blockade antibodies are approved for several cancer indications but pancreatic cancer has remained refractory. However, there are clinical data suggesting that stimulation of the CD40 pathway may be of interest for these patients. Oncolytic viruses armed with immunostimulatory genes represent an interesting approach. Herein we present LOAd703, a designed adenovirus armed with trimerized CD40L and 4-1BBL that activate the CD40 and 4-1BB pathways, respectively. Since many cells in the tumor stroma, including stellate cells, and the infiltrating immune cells express CD40 and some 4-1BB, we hypothesize that LOAd703 activates immunity and simultaneously modulates the biology of the tumor stroma. <p>Experimental design: Tumor-, stellate-, endothelial-, and immune cells were infected by LOAd703 and investigated by flow cytometry, proteomics and functional analyses.</p> <p>Results: LOAd703-infected pancreatic cell lines were killed by oncolysis and the virus was more effective than standard of care gemcitabine. In in vivo xenograft models, LOAd703 efficiently reduced established tumors and could be combined with gemcitabine for additional effect. Infected stellate- and tumor cells reduced factors that promote tumor growth (Spp-1, Gal-3, HGF, TGF-beta and collagen type I), while chemokines were increased. Molecules involved in lymphocyte migration were upregulated on infected endothelial cells. Dendritic cells were robustly stimulated by LOAd703 to produce co-stimulators, cytokines and chemokines, and such DCs potently expanded both antigen-specific T cells and NK cells. Conclusions: LOAd703 is a potent immune activator that modulates the stroma to support antitumor responses.
http://ift.tt/2qNkBw6
Immune correlates of GM-CSF and melanoma peptide vaccination in a randomized trial for the adjuvant therapy of resected high-risk melanoma (E4697)
Purpose: E4697 was a multi-center intergroup randomized placebo-controlled Phase III trial of adjuvant GM-CSF and/or a multi-epitope melanoma peptide vaccine for patients with completely resected, high-risk stage III/IV melanoma. <p>Experimental Design: 815 patients were enrolled from 12/99 to 10/06 into this 6-arm study. GM-CSF was chosen to promote the numbers and functions of dendritic cells (DC). The melanoma antigen peptide vaccine (Tyrosinase368-376 (370D), gp100209-217 (210M), MART-127-35) in Montanide was designed to promote melanoma specific CD8+ T cell responses.</p> <p>Results: Although the overall RFS and OS were not significantly improved with the vaccine or GM-CSF when compared with placebo, immunomodulatory effects were observed in peripheral blood and served as important correlates to this therapeutic study. Peripheral blood was examined to evaluate the impact of GM-CSF and/or the peptide vaccine on peripheral blood immunity and to investigate potential predictive or prognostic biomarkers. 11.3% of unvaccinated patients and 27.1% of vaccinated patients developed peptide-specific CD8+ T cell responses. HLA-A2+ patients who had any peptide-specific CD8+ T cell response at day +43 tended to have poorer OS in univariate analysis. Patients receiving GM-CSF had significant reduction in percentages of circulating myeloid dendritic cells (mDC) and plasmacytoid DC (pDC) at day +43. In a subset of patients who received GM-CSF, circulating myeloid-derived suppressor cells (MDSC), and anti-GM-CSF neutralizing antibodies (Nabs) were also modulated. The majority of patients developed anti-GM-CSF Nabs, which correlated with improved RFS and OS.</p> Conclusions: The assessment of cellular and humoral responses identified counter-intuitive immune system changes correlating with clinical outcome.
http://ift.tt/2qirySl
CHRONIC LYMPHOCYTIC LEUKEMIA WITH MUTATED IGHV4-34 RECEPTORS: SHARED AND DISTINCT IMMUNOGENETIC FEATURES AND CLINICAL OUTCOMES
Purpose:We sought to investigate if B cell receptor immunoglobulin (BcR IG) stereotypy is associated with particular clinicobiological features amongst chronic lymphocytic leukemia (CLL) patients expressing mutated BcR IG (M-CLL) encoded by the IGHV4-34 gene, and also ascertain whether these associations could refine prognostication.<br /> <p>Experimental Design: In a series of 19,907 CLL cases with available immunogenetic information, we identified 339 IGHV4-34 expressing cases assigned to one of the four largest stereotyped M-CLL subsets, namely subsets #4, #16, #29 and #201, and investigated in detail their clinicobiological characteristics and disease outcomes.</p> Results:We identified shared and subset-specific patterns of somatic hypermutation (SHM) amongst patients assigned to these subsets. The greatest similarity was observed between subsets #4 and #16, both including IgG-switched cases (IgG-CLL). In contrast, the least similarity was detected between subsets #16 and #201, the latter concerning IgM/D-expressing CLLs. Significant differences between subsets also involved disease stage at diagnosis and the presence of specific genomic aberrations. IgG subsets #4 and #16 emerged as particularly indolent with a significantly (p<0.05) longer time-to-first-treatment (TTFT) (median TTFT: not yet reached) compared to the IgM/D subsets #29 and #201 (median TTFT: 11 and 12 years, respectively).<br /><br />Conclusions:Our findings support the notion that BcR IG stereotypy further refines prognostication in CLL, superseding the immunogenetic distinction based solely on SHM load. Additionally, the observed distinct genetic aberration landscapes and clinical heterogeneity suggests that not all M-CLL cases are equal, prompting further research into the underlying biological background with the ultimate aim of tailored patient management.
http://ift.tt/2qNlxAA
Development and validation of an ultra-deep next-generation sequencing assay for testing of plasma cell-free DNA from patients with advanced cancer
Purpose: Tumor-derived cell-free DNA (cfDNA) in plasma can be used for molecular testing and provide an attractive alternative to tumor tissue. Commonly used PCR-based technologies can test for limited number of alterations at the time. Therefore, novel ultrasensitive technologies capable of testing for a broad spectrum of molecular alterations are needed to further personalized cancer therapy. <p>Experimental Design: We developed a highly sensitive ultra-deep next-generation sequencing (NGS) assay using reagents from TruSeqNano library preparation and NexteraRapid Capture target enrichment kits to generate plasma cfDNA sequencing libraries for mutational analysis in 61 cancer-related genes using common bioinformatics tools. The results were retrospectively compared to molecular testing of archival primary or metastatic tumor tissue obtained at different points of clinical care.</p> <p>Results: In a study of 55 patients with advanced cancer, the ultra-deep NGS assay detected 82% (complete detection) to 87% (complete and partial detection) of the aberrations identified in discordantly collected corresponding archival tumor tissue. Patients with a low variant allele frequency (VAF) of mutant cfDNA survived longer than those with a high VAF did (P=0.018). In patients undergoing systemic therapy, radiological response was positively associated with changes in cfDNA VAF (P=0.02), and compared with unchanged/increased mutant cfDNA VAF, decreased cfDNA VAF was associated with longer time to treatment failure (TTF; P=0.03).</p> <p>Conclusions: Ultra-deep NGS assay has good sensitivity compared to conventional clinical mutation testing of archival specimens. A high VAF in mutant cfDNA corresponded with shorter survival. Changes in VAF of mutated cfDNA were associated with TTF.
http://ift.tt/2qi8WBY
Williams-Beuren Syndrome and Congenital Lobar Emphysema: Uncommon Association with Common Pathology?
Introduction. Congenital lobar emphysema (CLE) and Williams-Beuren Syndrome are two rare conditions that have only been reported together in a single case study. Case Presentation. We report another case of a male Caucasian newborn with nonspecific initial respiratory distress, with detection of CLE on repeat chest X-ray on Day 25 of life and concurrent ventricular septal defect, supravalvular aortic stenosis, and branch pulmonary stenosis, in whom a 7q11.23 deletion consistent with Williams-Beuren Syndrome was made. Conclusion. A diagnosis of congenital lobar emphysema should prompt further screening for congenital heart disease and genetic deletion, and further research is needed to investigate the role of elastin gene mutation in the development of the neonatal lung.
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Assessment of the Albumin-Bilirubin (ALBI) Grade as a Prognostic Indicator for Hepatocellular Carcinoma Patients Treated With Radioembolization.
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Assessment of the Albumin-Bilirubin (ALBI) Grade as a Prognostic Indicator for Hepatocellular Carcinoma Patients Treated With Radioembolization.
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Optimization of diagnostic performance for differentiation of recurrence from radiation necrosis in patients with metastatic brain tumors using tumor volume-corrected 11 C-methionine uptake
Abstract
Background
Tumor to normal tissue ratio (T/N ratio) on 11C-methionine (11C-MET) positron emission tomography/computed tomography (PET/CT) is affected by variable factors. We investigated whether T/N ratio cutoff values corrected according to metabolic tumor volume (MTV) could improve the diagnostic performance of 11C-MET PET/CT for diagnosis of recurrence in patients with metastatic brain tumor.
Forty-eight patients with metastatic brain tumors underwent 11C-MET PET/CT for differential diagnosis between recurrence and radiation necrosis after gamma knife radiosurgery (GKR). Both T/N ratio and MTV were estimated in each lesion on 11C-MET PET/CT. The lesions were classified into three groups based on MTV criteria (≤ 0.5 cm3; > 0.5, ≤ 4.0 cm3; and > 4.0 cm3). The optimal cutoff values of the T/N ratio from receiver operating characteristic (ROC) curve were determined in each group (MTV-corrected) as well as total lesions (non-corrected). Finally, diagnostic performance of 11C-MET PET/CT was compared with the MTV-corrected cutoff values.
Results
Among 77 lesions, 51 were diagnosed with recurrence. The mean T/N ratio was 2.25 (± 1.12) for recurrent lesions and 1.44 (± 0.22) for radiation necrosis (P < 0.001). T/N ratio of 1.61 (non-corrected) provided the best sensitivity, specificity, and diagnostic accuracy (70.6, 80.8, and 74.0%, respectively). Using the MTV criteria, optimal cutoff values of the T/N ratios in each group were 1.23 (MTV ≤ 0.5 cm3), 1.54 (0.5 cm3 < MTV ≤ 4.0 cm3), and 1.85 (MTV > 4.0 cm3). In small-sized lesions (MTV ≤ 0.5 cm3), MTV-corrected cutoff values (1.23) could maintain favorable diagnostic performance with sensitivity, specificity, and diagnostic accuracy (70.0, 80.0, and 73.3%, respectively), compared to non-corrected cutoff values.
Conclusions
MTV-corrected cutoff values of T/N ratio could maintain the diagnostic performance of 11C-MET PET/CT in small sized, metastatic brain tumors. We expect our results to contribute to reproducible and standardized interpretation of 11C-MET PET/CT.
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Clinical and imaging-based prognostic factors in radioembolisation of liver metastases from colorectal cancer: a retrospective exploratory analysis
Abstract
Background
The aim of this study was to investigate the relationship between absorbed dose and response of colorectal cancer liver metastases treated with [90Y]-resin microspheres and to explore possible clinical and imaging derived prognostic factors.
Methods
FDG PET/CT was used to measure response of individual lesions to a measured absorbed dose, derived from post-treatment 90Y PET imaging. Predicted dose was also derived from planning [99mTc]-MAA SPECT data. Peak standardised uptake value and total lesion glycolysis (TLG) were explored as response measures, and compared to dose metrics including average dose (D avg), biologically effective dose, minimum dose to 70% of lesion volume and volume receiving at least 50 Gy. Prognostic factors examined included baseline TLG, RAS mutation status, FDG heterogeneity and dose heterogeneity. In an exploratory analysis, response and clinico-pathological variables were evaluated and compared to overall survival.
Results
Sixty-three lesions were analysed from 22 patients. Poor agreement was seen between predicted and measured dose values. TLG was a superior measure of response, and all dose metrics were significant prognostic factors, with a D avg of ~50 Gy derived as the critical threshold for a significant response (>50% reduction in TLG). No significant correlation was found between baseline TLG or RAS mutation status and response. Measured dose heterogeneity was a significant prognostic factor and when combined with D avg had a positive predictive value for response >80%. In the exploratory analysis for prognostic factors of survival, low hepatic tumour burden and mean reduction in TLG >65% were independently associated with improved overall survival.
Conclusions
Lesions receiving an average dose greater than 50 Gy are likely to have a significant response. For lesions receiving less than 50 Gy, dose heterogeneity is a significant prognostic factor. Lesions receiving an average dose less than 20 Gy are unlikely to respond. A reduction in TLG may be associated with improved overall survival.
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Optimization of diagnostic performance for differentiation of recurrence from radiation necrosis in patients with metastatic brain tumors using tumor volume-corrected 11 C-methionine uptake
Abstract
Background
Tumor to normal tissue ratio (T/N ratio) on 11C-methionine (11C-MET) positron emission tomography/computed tomography (PET/CT) is affected by variable factors. We investigated whether T/N ratio cutoff values corrected according to metabolic tumor volume (MTV) could improve the diagnostic performance of 11C-MET PET/CT for diagnosis of recurrence in patients with metastatic brain tumor.
Forty-eight patients with metastatic brain tumors underwent 11C-MET PET/CT for differential diagnosis between recurrence and radiation necrosis after gamma knife radiosurgery (GKR). Both T/N ratio and MTV were estimated in each lesion on 11C-MET PET/CT. The lesions were classified into three groups based on MTV criteria (≤ 0.5 cm3; > 0.5, ≤ 4.0 cm3; and > 4.0 cm3). The optimal cutoff values of the T/N ratio from receiver operating characteristic (ROC) curve were determined in each group (MTV-corrected) as well as total lesions (non-corrected). Finally, diagnostic performance of 11C-MET PET/CT was compared with the MTV-corrected cutoff values.
Results
Among 77 lesions, 51 were diagnosed with recurrence. The mean T/N ratio was 2.25 (± 1.12) for recurrent lesions and 1.44 (± 0.22) for radiation necrosis (P < 0.001). T/N ratio of 1.61 (non-corrected) provided the best sensitivity, specificity, and diagnostic accuracy (70.6, 80.8, and 74.0%, respectively). Using the MTV criteria, optimal cutoff values of the T/N ratios in each group were 1.23 (MTV ≤ 0.5 cm3), 1.54 (0.5 cm3 < MTV ≤ 4.0 cm3), and 1.85 (MTV > 4.0 cm3). In small-sized lesions (MTV ≤ 0.5 cm3), MTV-corrected cutoff values (1.23) could maintain favorable diagnostic performance with sensitivity, specificity, and diagnostic accuracy (70.0, 80.0, and 73.3%, respectively), compared to non-corrected cutoff values.
Conclusions
MTV-corrected cutoff values of T/N ratio could maintain the diagnostic performance of 11C-MET PET/CT in small sized, metastatic brain tumors. We expect our results to contribute to reproducible and standardized interpretation of 11C-MET PET/CT.
http://ift.tt/2rOva0t
Clinical and imaging-based prognostic factors in radioembolisation of liver metastases from colorectal cancer: a retrospective exploratory analysis
Abstract
Background
The aim of this study was to investigate the relationship between absorbed dose and response of colorectal cancer liver metastases treated with [90Y]-resin microspheres and to explore possible clinical and imaging derived prognostic factors.
Methods
FDG PET/CT was used to measure response of individual lesions to a measured absorbed dose, derived from post-treatment 90Y PET imaging. Predicted dose was also derived from planning [99mTc]-MAA SPECT data. Peak standardised uptake value and total lesion glycolysis (TLG) were explored as response measures, and compared to dose metrics including average dose (D avg), biologically effective dose, minimum dose to 70% of lesion volume and volume receiving at least 50 Gy. Prognostic factors examined included baseline TLG, RAS mutation status, FDG heterogeneity and dose heterogeneity. In an exploratory analysis, response and clinico-pathological variables were evaluated and compared to overall survival.
Results
Sixty-three lesions were analysed from 22 patients. Poor agreement was seen between predicted and measured dose values. TLG was a superior measure of response, and all dose metrics were significant prognostic factors, with a D avg of ~50 Gy derived as the critical threshold for a significant response (>50% reduction in TLG). No significant correlation was found between baseline TLG or RAS mutation status and response. Measured dose heterogeneity was a significant prognostic factor and when combined with D avg had a positive predictive value for response >80%. In the exploratory analysis for prognostic factors of survival, low hepatic tumour burden and mean reduction in TLG >65% were independently associated with improved overall survival.
Conclusions
Lesions receiving an average dose greater than 50 Gy are likely to have a significant response. For lesions receiving less than 50 Gy, dose heterogeneity is a significant prognostic factor. Lesions receiving an average dose less than 20 Gy are unlikely to respond. A reduction in TLG may be associated with improved overall survival.
http://ift.tt/2rfgQAT
Persistent immune stimulation exacerbates genetically-driven myeloproliferative disorders via stromal remodeling
Systemic immune stimulation has been associated with increased risk of myeloid malignancies, but the pathogenic link is unknown. We demonstrate in animal models that experimental systemic immune activation alters the bone marrow stromal microenvironment, disarranging extracellular matrix (ECM) microarchitecture, with down-regulation of SPARC and collagen-I and induction of complement activation. These changes were accompanied by a decrease in Treg frequency and by an increase in activated effector T cells. Under these conditions, hematopoietic precursors harboring nucleophosmin-1 (NPM1) mutation generated myeloid cells unfit for normal hematopoiesis but prone to immunogenic death, leading to neutrophil extracellular trap (NET) formation. NET fostered the progression of the indolent NPM1-driven myeloproliferation toward an exacerbated and proliferative dysplastic phenotype. Enrichment in NET structures was found in the bone marrow of patients with autoimmune disorders and in NPM1-mutated AML patients. Genes involved in NET formation in the animal model were used to design a NET-related inflammatory gene signature for human myeloid malignancies. This signature identified two AML subsets with different genetic complexity and different enrichment in NPM1 mutation and predicted the response to immunomodulatory drugs. Our results indicate that stromal/ECM changes and priming of bone marrow NETosis by systemic inflammatory conditions can complement genetic and epigenetic events towards the development and progression of myeloid malignancy.
http://ift.tt/2q9kr3w
Distinct roles of Hes1 in normal stem cells and tumor stem-like cells of the intestine
Cancer stem cells (CSC) have attracted attention as therapeutic targets, however, CSC-targeting therapy may disrupt normal tissue homeostasis because many CSC molecules are also expressed by normal stem cells (NSC). Here we demonstrate that NSC-specific and CSC-specific roles of the stem cell transcription factor Hes1 in the intestine enable the feasibility of a specific cancer therapy. Hes1 expression was upregulated in NSC and intestinal tumors. Lineage tracing experiments in adult mouse intestine revealed that Hes1 deletion in Lgr5+ or Bmi1+ NSC resulted in loss of self-renewal but did not perturb homeostasis. Further, in Lgr5+ NSC deletion of Hes1 stabilized β-catenin, limited tumor formation and prolonged host survival. Notably, in Lgr5+ or Dclk1+ tumor stem cells derived from established intestinal tumors, Hes1 deletion triggered immediate apoptosis, reducing tumor burden. Our results show how Hes1 plays different roles in NSC and CSC, in which Hes1 disruption leads to tumor regression without perturbing normal stem cell homeostasis, preclinically validating Hes1 as a cancer therapeutic target.
http://ift.tt/2qUau7c
Liver metastasis is facilitated by the adherence of circulating tumor cells to vascular fibronectin deposits
The interaction between circulating tumor cells (CTC) and endothelial cells during extravasation is a critical process during metastatic colonization, but its mechanisms remain poorly characterized. Here we report that the luminal side of liver blood vessels contains fibronectin deposits that are enriched in mice bearing primary tumors and are also present in vessels from human livers affected with metastases. Cancer cells attached to endothelial fibronectin deposits via talin1, a major component of focal adhesions. Talin1 depletion impaired cancer cell adhesion to the endothelium and transendothelial migration, resulting in reduced liver metastasis formation in vivo. Talin1 expression levels in patient CTC's correlated with prognosis and therapy response. Together, our findings uncover a new mechanism for liver metastasis formation involving an active contribution of hepatic vascular fibronectin and talin1 in cancer cells.
http://ift.tt/2q9tkdg
The damaging effect of passenger mutations on cancer progression
Genomic instability and high mutation rates cause cancer to acquire numerous mutations and chromosomal alterations during its somatic evolution, most are termed passengers because they do not confer cancer phenotypes. Evolutionary simulations and cancer genomic studies suggest that mildly deleterious passengers accumulate and can collectively slow cancer progression. Clinical data also suggest an association between passenger load and response to therapeutics, yet no causal link between the effects of passengers and cancer progression has been established. To assess this, we introduced increasing passenger loads into human cell lines and immunocompromised mouse models. We found that passengers dramatically reduced proliferative fitness (~3% per Mb), slowed tumor growth, and reduced metastatic progression. We developed new genomic measures of damaging passenger load that can accurately predicted the fitness costs of passengers in cell lines and in human breast cancers. We conclude that genomic instability and elevated load of DNA alterations in cancer is a double-edged sword: it accelerates the accumulation of adaptive drivers, but incurs a harmful passenger load that can outweigh driver benefit. The effects of passenger alterations on cancer fitness were unrelated to enhanced immunity, as our tests were performed either in cell culture or in immunocompromised animals. Our findings refute traditional paradigms of passengers as neutral events, suggesting that passenger load reduces the fitness of cancer cells and slows or prevents progression of both primary and metastatic disease. The anti-tumor effects of chemotherapies can in part be due to induction of genomic instability and increased passenger load.
http://ift.tt/2qUt52T
Immune checkpoint blockade, immunogenic chemotherapy or IFN-{alpha} blockade boost the local and abscopal effects of oncolytic virotherapy
Athough the clinical efficacy of oncolytic viruses has been demonstrated for local treatment, the ability to induce immune-mediated regression of distant metastases is still poorly documented. We report here that the engineered oncolytic vaccinia virus VVWR-TK-RR--Fcu1 can induce immunogenic cell death and generate a systemic immune response. Effects on tumor growth and survival was largely driven by CD8+ T cells, and immune cell infiltrate in the tumor could be reprogrammed towards a higher ratio of effector T cells to regulatory CD4+ T cells. The key role of type 1-IFN pathway in oncolytic virotherapy was also highlighted, as we observed a strong abscopal response in Ifnar-/- tumors. In this model, single administration of virus directly into the tumors one one flank led to regression in the contralateral flank. Moreover, these effects were further enhanced when oncolytic treatment was combined with immunogenic chemotherapy or with immune checkpoint blockade. Taken together, our results suggest how to safely improve the efficacy of local oncolytic virotherapy in patients whose tumors are characterized by dysregulated IFN-α signaling.
http://ift.tt/2qUejJr
3D mathematical modeling of glioblastoma suggests that transdifferentiated vascular endothelial cells mediate resistance to current standard-of-care therapy
Glioblastoma (GBM), the most aggressive brain tumor in human patients, is decidedly heterogeneous and highly vascularized. Glioma stem/initiating cells (GSC) are found to play a crucial role by increasing cancer aggressiveness and promoting resistance to therapy. Recently, crosstalk between GSC and vascular endothelial cells has been shown to significantly promote GSC self-renewal and tumor progression. Further, GSC also transdifferentiate into bona-fide vascular endothelial cells (GEC), which inherit mutations present in GSC and are resistant to traditional anti-angiogenic therapies. Here we use 3D mathematical modeling to investigate GBM progression and response to therapy. The model predicted that GSC drive invasive fingering and that GEC spontaneously form a network within the hypoxic core, consistent with published experimental findings. Standard-of-care treatments using DNA-targeted therapy (radiation/chemo) together with anti-angiogenic therapies, reduced GBM tumor size but increased invasiveness. Anti-GEC treatments blocked the GEC support of GSC and reduced tumor size but led to increased invasiveness. Anti-GSC therapies that promote differentiation or disturb the stem cell niche effectively reduced tumor invasiveness and size, but were ultimately limited in reducing tumor size because GEC maintain GSC. Our study suggests that a combinatorial regimen targeting the vasculature, GSC, and GEC, using drugs already approved by the FDA, can reduce both tumor size and invasiveness and could lead to tumor eradication.
http://ift.tt/2q9at22
SIRT3-mediated dimerization of IDH2 directs cancer cell metabolism and tumor growth
The isocitrate dehydrogenase IDH2 produces α-ketoglutarate by oxidizing isocitrate, linking glucose metabolism to oxidative phosphorylation. In this study, we report that loss of SIRT3 increases acetylation of IDH2 at lysine 413 (IDH2-K413-Ac), thereby decreasing its enzymatic activity by reducing IDH2 dimer formation. Expressing a genetic acetylation mimetic IDH2 mutant (IDH2K413Q) in cancer cells decreased IDH2 dimerization and enzymatic activity and increased cellular reactive oxygen species (ROS) and glycolysis, suggesting a shift in mitochondrial metabolism. Concurrently, overexpression of IDH2K413Q promoted cell transformation and tumorigenesis in nude mice, resulting in a tumor-permissive phenotype. Immunohistochemical staining showed that IDH2 acetylation was elevated in high-risk luminal B patients relative to low-risk luminal A patients. Overall, these results suggest a potential relationship between SIRT3 enzymatic activity, IDH2-K413 acetylation-determined dimerization, and a cancer-permissive phenotype.
http://ift.tt/2qTU276
Dual inhibition of NOX2 and receptor tyrosine kinase by BJ-1301 enhances anticancer therapy efficacy via suppression of autocrine stimulatory factors in lung cancer
NADPH oxidase-derived reactive oxygen species (ROS) potentiate receptor tyrosine kinase (RTK) signalling, resulting in enhanced angiogenesis and tumor growth. In the present study, we report that BJ-1301, a hybrid of pyridinol and alpha-tocopherol, exerts anticancer effects by dual inhibition of NADPH oxidase and RTK activities in endothelial and lung cancer cells. BJ-1301 suppresses ROS production by blocking translocation of NADPH oxidase cytosolic subunits to the cell membrane, thereby inhibiting activation. The potency of RTK-inhibition by BJ-1301 was lower than that of sunitinib (a multi-RTK inhibitor), but the inhibition of downstream signaling pathways (e.g. ROS generation) and subsequent biological changes (e.g., NOX2 induction) by BJ-1301 was superior. Consistently, BJ-1301 inhibited cisplatin-resistant lung cancer cell proliferation more than sunitinib did. In xenograft chick or mouse tumor models, BJ-1301 inhibited lung tumor growth, to an extent greater than that of sunitinib or cisplatin. Treatments with BJ-1301 induced regression of tumor growth, potentially due to downregulation of autocrine stimulatory ligands for RTKs, such as transforming growth factor-α and stem cell factor, in tumor tissues. Taken together, the present study demonstrates that BJ-1301 is a promising anti-cancer drug for the treatment of lung cancer.
http://ift.tt/2q9u2Ya
Distinct roles of Hes1 in normal stem cells and tumor stem-like cells of the intestine
Cancer stem cells (CSC) have attracted attention as therapeutic targets, however, CSC-targeting therapy may disrupt normal tissue homeostasis because many CSC molecules are also expressed by normal stem cells (NSC). Here we demonstrate that NSC-specific and CSC-specific roles of the stem cell transcription factor Hes1 in the intestine enable the feasibility of a specific cancer therapy. Hes1 expression was upregulated in NSC and intestinal tumors. Lineage tracing experiments in adult mouse intestine revealed that Hes1 deletion in Lgr5+ or Bmi1+ NSC resulted in loss of self-renewal but did not perturb homeostasis. Further, in Lgr5+ NSC deletion of Hes1 stabilized β-catenin, limited tumor formation and prolonged host survival. Notably, in Lgr5+ or Dclk1+ tumor stem cells derived from established intestinal tumors, Hes1 deletion triggered immediate apoptosis, reducing tumor burden. Our results show how Hes1 plays different roles in NSC and CSC, in which Hes1 disruption leads to tumor regression without perturbing normal stem cell homeostasis, preclinically validating Hes1 as a cancer therapeutic target.
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Liver metastasis is facilitated by the adherence of circulating tumor cells to vascular fibronectin deposits
The interaction between circulating tumor cells (CTC) and endothelial cells during extravasation is a critical process during metastatic colonization, but its mechanisms remain poorly characterized. Here we report that the luminal side of liver blood vessels contains fibronectin deposits that are enriched in mice bearing primary tumors and are also present in vessels from human livers affected with metastases. Cancer cells attached to endothelial fibronectin deposits via talin1, a major component of focal adhesions. Talin1 depletion impaired cancer cell adhesion to the endothelium and transendothelial migration, resulting in reduced liver metastasis formation in vivo. Talin1 expression levels in patient CTC's correlated with prognosis and therapy response. Together, our findings uncover a new mechanism for liver metastasis formation involving an active contribution of hepatic vascular fibronectin and talin1 in cancer cells.
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The damaging effect of passenger mutations on cancer progression
Genomic instability and high mutation rates cause cancer to acquire numerous mutations and chromosomal alterations during its somatic evolution, most are termed passengers because they do not confer cancer phenotypes. Evolutionary simulations and cancer genomic studies suggest that mildly deleterious passengers accumulate and can collectively slow cancer progression. Clinical data also suggest an association between passenger load and response to therapeutics, yet no causal link between the effects of passengers and cancer progression has been established. To assess this, we introduced increasing passenger loads into human cell lines and immunocompromised mouse models. We found that passengers dramatically reduced proliferative fitness (~3% per Mb), slowed tumor growth, and reduced metastatic progression. We developed new genomic measures of damaging passenger load that can accurately predicted the fitness costs of passengers in cell lines and in human breast cancers. We conclude that genomic instability and elevated load of DNA alterations in cancer is a double-edged sword: it accelerates the accumulation of adaptive drivers, but incurs a harmful passenger load that can outweigh driver benefit. The effects of passenger alterations on cancer fitness were unrelated to enhanced immunity, as our tests were performed either in cell culture or in immunocompromised animals. Our findings refute traditional paradigms of passengers as neutral events, suggesting that passenger load reduces the fitness of cancer cells and slows or prevents progression of both primary and metastatic disease. The anti-tumor effects of chemotherapies can in part be due to induction of genomic instability and increased passenger load.
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Persistent immune stimulation exacerbates genetically-driven myeloproliferative disorders via stromal remodeling
Systemic immune stimulation has been associated with increased risk of myeloid malignancies, but the pathogenic link is unknown. We demonstrate in animal models that experimental systemic immune activation alters the bone marrow stromal microenvironment, disarranging extracellular matrix (ECM) microarchitecture, with down-regulation of SPARC and collagen-I and induction of complement activation. These changes were accompanied by a decrease in Treg frequency and by an increase in activated effector T cells. Under these conditions, hematopoietic precursors harboring nucleophosmin-1 (NPM1) mutation generated myeloid cells unfit for normal hematopoiesis but prone to immunogenic death, leading to neutrophil extracellular trap (NET) formation. NET fostered the progression of the indolent NPM1-driven myeloproliferation toward an exacerbated and proliferative dysplastic phenotype. Enrichment in NET structures was found in the bone marrow of patients with autoimmune disorders and in NPM1-mutated AML patients. Genes involved in NET formation in the animal model were used to design a NET-related inflammatory gene signature for human myeloid malignancies. This signature identified two AML subsets with different genetic complexity and different enrichment in NPM1 mutation and predicted the response to immunomodulatory drugs. Our results indicate that stromal/ECM changes and priming of bone marrow NETosis by systemic inflammatory conditions can complement genetic and epigenetic events towards the development and progression of myeloid malignancy.
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Immune checkpoint blockade, immunogenic chemotherapy or IFN-{alpha} blockade boost the local and abscopal effects of oncolytic virotherapy
Athough the clinical efficacy of oncolytic viruses has been demonstrated for local treatment, the ability to induce immune-mediated regression of distant metastases is still poorly documented. We report here that the engineered oncolytic vaccinia virus VVWR-TK-RR--Fcu1 can induce immunogenic cell death and generate a systemic immune response. Effects on tumor growth and survival was largely driven by CD8+ T cells, and immune cell infiltrate in the tumor could be reprogrammed towards a higher ratio of effector T cells to regulatory CD4+ T cells. The key role of type 1-IFN pathway in oncolytic virotherapy was also highlighted, as we observed a strong abscopal response in Ifnar-/- tumors. In this model, single administration of virus directly into the tumors one one flank led to regression in the contralateral flank. Moreover, these effects were further enhanced when oncolytic treatment was combined with immunogenic chemotherapy or with immune checkpoint blockade. Taken together, our results suggest how to safely improve the efficacy of local oncolytic virotherapy in patients whose tumors are characterized by dysregulated IFN-α signaling.
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3D mathematical modeling of glioblastoma suggests that transdifferentiated vascular endothelial cells mediate resistance to current standard-of-care therapy
Glioblastoma (GBM), the most aggressive brain tumor in human patients, is decidedly heterogeneous and highly vascularized. Glioma stem/initiating cells (GSC) are found to play a crucial role by increasing cancer aggressiveness and promoting resistance to therapy. Recently, crosstalk between GSC and vascular endothelial cells has been shown to significantly promote GSC self-renewal and tumor progression. Further, GSC also transdifferentiate into bona-fide vascular endothelial cells (GEC), which inherit mutations present in GSC and are resistant to traditional anti-angiogenic therapies. Here we use 3D mathematical modeling to investigate GBM progression and response to therapy. The model predicted that GSC drive invasive fingering and that GEC spontaneously form a network within the hypoxic core, consistent with published experimental findings. Standard-of-care treatments using DNA-targeted therapy (radiation/chemo) together with anti-angiogenic therapies, reduced GBM tumor size but increased invasiveness. Anti-GEC treatments blocked the GEC support of GSC and reduced tumor size but led to increased invasiveness. Anti-GSC therapies that promote differentiation or disturb the stem cell niche effectively reduced tumor invasiveness and size, but were ultimately limited in reducing tumor size because GEC maintain GSC. Our study suggests that a combinatorial regimen targeting the vasculature, GSC, and GEC, using drugs already approved by the FDA, can reduce both tumor size and invasiveness and could lead to tumor eradication.
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SIRT3-mediated dimerization of IDH2 directs cancer cell metabolism and tumor growth
The isocitrate dehydrogenase IDH2 produces α-ketoglutarate by oxidizing isocitrate, linking glucose metabolism to oxidative phosphorylation. In this study, we report that loss of SIRT3 increases acetylation of IDH2 at lysine 413 (IDH2-K413-Ac), thereby decreasing its enzymatic activity by reducing IDH2 dimer formation. Expressing a genetic acetylation mimetic IDH2 mutant (IDH2K413Q) in cancer cells decreased IDH2 dimerization and enzymatic activity and increased cellular reactive oxygen species (ROS) and glycolysis, suggesting a shift in mitochondrial metabolism. Concurrently, overexpression of IDH2K413Q promoted cell transformation and tumorigenesis in nude mice, resulting in a tumor-permissive phenotype. Immunohistochemical staining showed that IDH2 acetylation was elevated in high-risk luminal B patients relative to low-risk luminal A patients. Overall, these results suggest a potential relationship between SIRT3 enzymatic activity, IDH2-K413 acetylation-determined dimerization, and a cancer-permissive phenotype.
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Dual inhibition of NOX2 and receptor tyrosine kinase by BJ-1301 enhances anticancer therapy efficacy via suppression of autocrine stimulatory factors in lung cancer
NADPH oxidase-derived reactive oxygen species (ROS) potentiate receptor tyrosine kinase (RTK) signalling, resulting in enhanced angiogenesis and tumor growth. In the present study, we report that BJ-1301, a hybrid of pyridinol and alpha-tocopherol, exerts anticancer effects by dual inhibition of NADPH oxidase and RTK activities in endothelial and lung cancer cells. BJ-1301 suppresses ROS production by blocking translocation of NADPH oxidase cytosolic subunits to the cell membrane, thereby inhibiting activation. The potency of RTK-inhibition by BJ-1301 was lower than that of sunitinib (a multi-RTK inhibitor), but the inhibition of downstream signaling pathways (e.g. ROS generation) and subsequent biological changes (e.g., NOX2 induction) by BJ-1301 was superior. Consistently, BJ-1301 inhibited cisplatin-resistant lung cancer cell proliferation more than sunitinib did. In xenograft chick or mouse tumor models, BJ-1301 inhibited lung tumor growth, to an extent greater than that of sunitinib or cisplatin. Treatments with BJ-1301 induced regression of tumor growth, potentially due to downregulation of autocrine stimulatory ligands for RTKs, such as transforming growth factor-α and stem cell factor, in tumor tissues. Taken together, the present study demonstrates that BJ-1301 is a promising anti-cancer drug for the treatment of lung cancer.
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Seven fractions to deliver partial breast irradiation: the toxicity is Low
To assess toxicity and clinical outcome, in breast cancer patients treated with external beam partial breast irradiation (PBI) consisting of 35 Gy in 7 daily fractions (5 Gy/fraction).
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Seven fractions to deliver partial breast irradiation: the toxicity is Low
To assess toxicity and clinical outcome, in breast cancer patients treated with external beam partial breast irradiation (PBI) consisting of 35 Gy in 7 daily fractions (5 Gy/fraction).
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Effects of Adjuvant Radiotherapy in Patients With Synovial Sarcoma
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CNS Hemangiopericytoma: A Systematic Review of 523 Patients
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Complete Neoadjuvant Treatment for Rectal Cancer: The Brown University Oncology Group CONTRE Study
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Longitudinal DSC-MRI for Distinguishing Tumor Recurrence From Pseudoprogression in Patients With a High-grade Glioma
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Clinical, Radiographic, and Pathologic Findings in Patients Undergoing Reoperation Following Radiation Therapy and Temozolomide for Newly Diagnosed Glioblastoma
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Predictors and Patterns of Local, Regional, and Distant Failure in Squamous Cell Carcinoma of the Vulva
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