Publication date: Available online 20 September 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Kelsey Brunskill, Timothy K. Nguyen, R. Gabriel Boldt, Alexander V. Louie, Andrew Warner, Lawrence B. Marks, David A. Palma
PurposePeer review is a recommended component of quality assurance in radiation oncology, however it is resource-intensive and its effect on patient care is not well understood. We conducted a systematic review of the literature to assess the reported clinical impact of peer review on radiotherapy treatment plans.MethodsA systematic review of the English literature was executed following PRISMA guidelines, including MEDLINE, EMBASE, and abstracts published from major radiation oncology scientific meeting proceedings. For inclusion, studies were required to report the impact of peer review on at least one element of treatment planning (e.g. target volume or organat- risk delineation, dose prescription, or dosimetry).ResultsThe initial search strategy identified 882 potentially eligible studies with 11 meeting inclusion criteria for full-text review and final analysis. Across a total of 11,491 patient cases, peer review programs led to modifications in a weighted mean of 10.8% of radiation treatment plans. Five studies differentiated between major and minor changes, and reported weighted mean rates of change of 2.7% and 7.3% respectively. The most common changes related to target volume delineation (45.2% of changed plans), dose prescription or written directives (24.4%), and non-target volume delineation or normal tissue sparing (7.5%).ConclusionsOur findings suggest that peer review leads to changes in clinical care in approximately 1 out every 9 cases overall. This is similar to reported rates of change in peer review studies from other oncology-related specialties, such as radiology and pathology.
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Τρίτη 20 Σεπτεμβρίου 2016
Does Peer Review of Radiation Plans Impact Clinical Care? A Systematic Review of the Literature
Genetic Variants in CD44 and MAT1A Confer Susceptibility to Acute Skin Reaction in Breast Cancer Patients Undergoing Radiotherapy
Publication date: Available online 20 September 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Kamalesh Dattaram Mumbrekar, Satish Rao Bola Sadashiva, Shama Prasada Kabekoddu, Donald Jerard Fernandes, Bejadi Manjunath Vadhiraja, Tomo Suga, Yoshimi Shoji, Fumiaki Nakayama, Takashi Imai, Kapaettu Satyamoorthy
PurposeHeterogeneity in radiotherapy (RT) induced normal tissue toxicity is observed in 10% of cancer patients, limiting the therapeutic outcome. Besides, treatment related factors, normal tissue adverse reactions are also manifested from genetic alterations in genes of distinct pathways majorly involving DNA damage-repair, inflammatory cytokine, cell cycle regulation and antioxidant response. Therefore, the common sequence variants in these radioresponsive genes may modify the severity of normal tissue toxicity and identification of the same may have clinical relevance as a predictive biomarker.
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Experimental platform for ultra-high dose rate FLASH irradiation of small animals using a clinical linear accelerator
Publication date: Available online 20 September 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Emil Schüler, Stefania Trovati, Gregory King, Frederick Lartey, Marjan Rafat, Manuel Villegas, A. Joe Praxel, Billy W. Loo, Peter G. Maxim
Backgroundand Purpose: A key factor limiting the effectiveness of radiation therapy is normal tissue toxicity, and recent preclinical data shows that ultra-high dose rate irradiation (>50 Gy/s, "FLASH") potentially mitigates this effect. However, research in this field has so far been strongly limited by the availability of FLASH irradiators suitable for small animal experiments. We present a simple methodological approach for FLASH electron small animal irradiation with a clinically available LINAC.Material and MethodsWe investigated the FLASH irradiation potential of a Varian Clinac 21EX in both clinical mode and after tuning of the LINAC. We performed detailed FLUKA Monte Carlo and experimental dosimetric characterization at multiple experimental locations within the LINAC head.ResultsAverage dose rates of up to 74 Gy/s were achieved in clinical mode, while the dose rate after tuning exceeded 900 Gy/s. We obtained 220 Gy/s at 1 cm depth for a >4 cm field size with 90% homogeneity throughout a 2 cm thick volume.ConclusionsWe present an approach for using a clinical linear accelerator for FLASH irradiations. We obtained dose rates exceeding 200 Gy/s following simple tuning of the LINAC with excellent dosimetric properties for small animal experiments. This allows for increased availability of FLASH irradiation to the general research community.
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A new functional IDH2 genetic variant is associated with the risk of lung cancer
Abstract
Recently, mutations in isocitrate dehydrogenase 1/2 (IDH1/2) were discovered in 70% of low-grade glioma and secondary glioblastoma multiforme. The discovery of an oncogenic function and the identification of onco-metabolites of IDH1/2 support new roles for metabolism in cancer. For example, some evidence indicates that IDH2 might also exhibit oncogenic functions by promoting cellular metabolism and cancer cell growth. We examined the association between IDH2 rs11540478 and lung cancer risk in 262 lung cancer patient cases and 602 healthy control subjects and also investigated the biological function of rs11540478 in vivo. We found that a higher risk was observed in lung cancer patient carriers of rs11540478 TT and CT compared with CC carriers(OR = 1.44; 95% CI = 1.04-2.00; p = 0.03). The frequency of IDH2 rs11540478 TT and CT carriers was decreased in healthy individuals between the ages of 50-77 compared to those aged 30-49 (OR = 0.67; 95% CI = 0.47-0.96; p = 0.03). Functional analysis showed the effect of rs11540478 on IDH2 expression and lung cancer cell viability, with higher IDH2 expression and cell viability among T allele compared with C allele. IDH2 mRNA was higher in peripheral blood lymphocytes from lung cancer patients compared to healthy subjects. Herein, for the first time we identified IDH2 rs11540478 as a new susceptibility locus for lung cancer. The effect of rs11540478 on mRNA expression of IDH2 and lung cancer cell viability might provide new insight for the genetic basis of lung cancer. This article is protected by copyright. All rights reserved
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Exploiting agonist biased signaling of chemokines to target cancer
Abstract
As knowledge of growth-independent functions of cancer cells is expanding, exploration into the role of chemokines in modulating cancer pathogenesis, particularly metastasis, continues to develop. However, more study into the mechanisms whereby chemokines direct the migration of cancer cells is needed before specific therapies can be generated to target metastasis. Herein, we draw attention to the longstanding conundrum in the field of chemokine biology that chemokines stimulate migration in a biphasic manner; and explore this phenomenon's impact on chemokine function in the context of cancer. Typically, low concentrations of chemokines lead to chemotactic migration and higher concentrations halt migration. The signaling mechanisms that govern this phenomenon remain unclear. Over the last decade we have defined a novel signaling mechanism for regulation of chemokine migration through ligand oligomerization and biased agonist signaling. We provide insight into this new paradigm for chemokine signaling and discuss how it will impact future exploration into chemokine function and biology. In the pursuit of producing more novel cancer therapies, we suggest a framework for pharmaceutical application of the principles of chemokine oligomerization and biased agonist signaling in cancer. This article is protected by copyright. All rights reserved
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Anthocyanidins inhibit epithelial-mesenchymal transition through a TGF-β/Smad2 signaling pathway in glioblastoma cells
ABSTRACT
Epidemiological studies have convincingly demonstrated that diets rich in fruits and vegetables play an important role in preventing cancer due to their polyphenol content. Among polyphenols, the anthocyanidins are known to possess anti-inflammatory, cardioprotective, anti-angiogenic and anti-carcinogenic properties. Despite the well-known role of transforming growth factor-β (TGF-β) in high grade gliomas, the impact of anthocyanidins on TGF-β-induced epithelial mesenchymal transition (EMT), a process that allows benign tumor cells to infiltrate surrounding tissues, remains poorly understood. The objective of this study is to investigate the impact of anthocyanidins such as cyanidin (Cy), delphinidin (Dp), malvidin (Mv), pelargonidin (Pg) and petunidin (Pt) on TGF-β-induced EMT and to determine the mechanism(s) underlying such action. Human U-87 glioblastoma (U-87 MG) cells were treated with anthocyanidins prior to, along with or following the addition of TGF-β. We found that anthocyanidins differently affected TGF-β-induced EMT, depending on the treatment conditions. Dp was the most potent EMT inhibitor through its inhibitory effect on the TGF-β Smad and non-Smad signaling pathways. These effects altered expression of the EMT mesenchymal markers fibronectin and Snail, as well as markedly reducing U-87 MG cell migration. Our study highlights a new action of anthocyanidins against EMT that supports their beneficial health and chemopreventive effects in dietary-based strategies against cancer. This article is protected by copyright. All rights reserved
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Down-regulation of β-catenin and the associated migration ability by Taiwanin C in arecoline and 4-NQO-induced oral cancer cells via GSK-3β activation
Abstract
Cancer is one of the leading causes of death worldwide, and oral squamous cell carcinoma (OSCC) accounts for almost a sixth of all reported cancers. Arecoline, from areca nut is known to enhance carcinogenesis in oral squamous cells. The objective of this study is to determine the effect of Taiwanin C, from Taiwania cryptomerioides Hayata against Arecoline-associated carcinogenesis. An OSCC model was created in C57BL/6J Narl mice by administrating 0.5 mg/mL arecoline with 0.2 mg/mL 4-NQO carcinogen for 8 and 28 weeks to mimic the etiology of oral cancer patients in Asia. Mice were sacrificed and two cell lines, T28 from the tumor and N28 cancerous cell line from the surrounding non tumor area, were established. Taiwanin C showed effective anti-tumor activity in nude mice models. Taiwanin C significantly inhibited the cell viability of T28 cells in a dose dependent manner, but did not inflict any effect on N28 normal cells. Taiwanin C treatment inhibited the migration ability of T28 cells in a dose dependent manner as determined by wound healing and migration assays. Taiwanin C also reduced the levels of β-catenin and its downstream metastatic proteins, Tbx3 and c-Myc. Besides, Taiwanin C inhibited the nuclear accumulation of β-catenin and induced β-catenin degradation via proteasome-mediated pathway. Moreover, Taiwanin C enhanced GSK-3β and reduced the p-ser9 GSK-3β protein level to inactivate Wnt signaling. Taken together, Taiwanin C blocked the cell migration effects of T28 cells mediated through the activation of GSK-3β to enhance protein degradation and reduce nuclear accumulation of β-catenin. This article is protected by copyright. All rights reserved
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Ephrin-B2 overexpression predicts for poor prognosis and response to therapy in solid tumors
Abstract
Ephrin B2 is variably expressed on tumor cells and its blockade has been shown to inhibit angiogenesis in animal models of pancreatic, colorectal, lung and head and neck squamous cell carcinomas. However, the implications of ephrinB2 expression in cancer patients have remained elusive. In this study, we analyzed the cancer genome atlas (TCGA) for ephrinB2 expression. We report significant correlations between EFNB2 expression, overall survival and disease-free survival in head and neck squamous cell carcinoma (HNSCC, n = 519), pancreatic adenocarcinoma (n = 186) and bladder urothelial carcinoma (n = 410). In HNSCC patients, high EFNB2 mRNA expression was associated with tumor HPV negativity, oral cavity location, alcohol intake, higher TP53 mutation, and EGFR amplification. EphrinB2 overexpression also correlated with worse response to chemotherapy and radiotherapy. The therapeutic potential of blocking ephrinB2 was validated in HNSCC patient-derived tumor xenografts and showed significant improvement in survival and tumor growth delay. Our data shows that ephrinB2 overexpression can serve as a critical biomarker for patient prognosis and response to therapy. These results should guide design of future clinical trials exploring EphrinB2 inhibition in cancer patients. This article is protected by copyright. All rights reserved
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KITENIN functions as a fine regulator of ErbB4 expression level in colorectal cancer via protection of ErbB4 from E3-ligase Nrdp1-mediated degradation
ABSTRACT
Understanding the complex biological functions of E3-ubiquitin ligases may facilitate the development of mechanism-based anti-cancer drugs. We recently identified that the KITENIN/ErbB4-Dvl2-c-Jun axis works as a novel unconventional downstream signal of epidermal growth factor (EGF) in colorectal cancer (CRC) tissues. Here we addressed whether E3-ubiquitin ligases are required for operation of this axis. We found that Nrdp1, an E3-ligase for ErbB3/ErbB4, interacted with KITENIN (KAI1 C-terminal interacting tetraspanin) to form a functional KITENIN/ErbB4/Nrdp1 complex and is responsible for down-regulating Dvl2 within this complex. Interestingly, ErbB4 was resistant to degradation by Nrdp1 in KITENIN/Nrdp1-co-transfected CRC cells, and KITENIN bound to the C-terminal coiled-coil domain of Nrdp1. Chemical blockade of ErbB kinase did not block the action of EGF to increase in total/phospho-ErbB4 and phospho-ERK in KITENIN/ErbB4-cotransfected cells, whereas it blocked the action of EGF in ErbB4 alone-transfected CRC cells. In human CRC tissues, higher expressions of ErbB4 and KITENIN and lower expression of Dvl2 was observed in stage IV samples than in stage I, but a low level of Nrdp1 was expressed in both stages and it did not differ significantly by stage. These results indicated that Nrdp1 is necessary for the reduction in Dvl2 to generate c-Jun in the EGF-KITENIN/ErbB4-c-Jun axis, but more importantly, elevated KITENIN protects KITENIN-bound ErbB4 from Nrdp1-mediated degradation via physical collaboration between the KITENIN/ErbB4 complex and Nrdp1, but not via modulation of ErbB kinase activity. Thus, KITENIN functions in the maintenance of a higher expression level of ErbB4 in advanced CRC tissues, independent of ubiquitin-mediated degradation via Nrdp1. This article is protected by copyright. All rights reserved
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Prognostic value of phosphorylated Raf kinase inhibitory protein at serine 153 and its predictive effect on the clinical response to radiotherapy in nasopharyngeal carcinoma
Radiation is an effective treatment against nasopharyngeal carcinoma (NPC). However, radioresistance-induced locoregional recurrence remains as a major cause of treatment failure. Therefore, radiosensitivity i...
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Deformable image registration for adaptive radiotherapy with guaranteed local rigidity constraints
Deformable image registration (DIR) is a key component in many radiotherapy applications. However, often resulting deformations are not satisfying, since varying deformation properties of different anatomical ...
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TIMP1 is a prognostic marker for the progression and metastasis of colon cancer through FAK-PI3K/AKT and MAPK pathway
Abstract
Background
Tissue inhibitor matrix metalloproteinase 1 (TIMP1) plays a vital role in carcinogenesis, yet its precise functional roles and regulation remain unclear. In this study, we aim to investigate its biological function and clinical significance in human colon cancer.
Methods
We analyzed the expression of TIMP1 in both public database (Oncomine and TCGA) and 94 cases of primary colon cancer and matched normal colon tissue specimens. The underlying mechanisms of altered TIMP1 expression on cell tumorigenesis, proliferation, and metastasis were explored in vitro and in vivo.
Results
TIMP1 was overexpressed in colon tumorous tissues and lymph node metastasis specimens than in normal tissues. The aberrant expression of TIMP1 was significantly associated with the regional lymph node metastasis (p = 0.033), distant metastasis (p = 0.039), vascular invasion (p = 0.024) and the American Joint Committee on Cancer (AJCC) stage (p = 0.026). Cox proportional hazards model showed that TIMP1 was an independent prognostic indicator of disease-free survival (HR = 2.603, 95 % CI: 1.115–6.077, p = 0.027) and overall survival (HR = 2.907, 95 % CI: 1.254–6.737, p = 0.013) for patients with colon cancer. Consistent with this, our findings highlight that suppression of TIMP1 expression decreased proliferation, and metastasis but increased apoptosis by inducing TIMP1 specific regulated FAK-PI3K/AKT and MAPK pathway.
Conclusion
TIMP1 might play an important role in promoting tumorigenesis and metastasis of human colon cancer and function as a potential prognostic indicator for colon cancer.
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Proconvulsant effects of the ketogenic diet in electroshock-induced seizures in mice
Abstract
Among non-pharmacological treatments, the ketogenic diet (KD) has the strongest demonstrated evidence of clinical success in drug resistant epilepsy. In an attempt to model the anticonvulsant effects of the KD pre-clinically, the present study assessed the effects of the KD against electroshock-induced convulsions in mice. After confirming that exposure to the KD for 2 weeks resulted in stable ketosis and hypoglycemia, mice were exposed to electroshocks of various intensities to establish general seizure susceptibility. When compared to mice fed the standard rodent chow diet (SRCD), we found that mice fed the KD were more sensitive to electroconvulsions as reflected by a significant decrease in seizure threshold (3.86 mA in mice on the KD vs 7.29 mA in mice on the SRCD; P < 0.05) in the maximal electroshock seizure threshold (MEST) test. To examine if this increased seizure sensitivity to electroconvulsions produced by the KD would affect anticonvulsant effects of antiepileptic drugs (AEDs), anticonvulsant potencies of carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and valproate (VPA) against maximal electroshock (MES)-induced convulsions were compared in mice fed the KD and SRCD. We found that potencies of all AEDs studied were decreased in mice fed the KD in comparison to those on the SRCD, with decreases in the anticonvulsant potencies ranging from 1.4 fold (PB) to 1.7 fold (PHT). Finally, the lack of differences in brain exposures of the AEDs studied in mice fed the KD and SRCD ruled out a pharmacokinetic nature of the observed findings. Taken together, exposure to the KD in the present study had an overall pro-convulsant effect. Since electroconvulsions require large metabolic reserves to support their rapid spread throughout the brain and consequent generalized tonic-clonic convulsions, this effect may be explained by a high energy state produced by the KD in regards to increased energy storage and utilization.
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Symptom Experiences in Metastatic Breast Cancer Patients: Relationships to Activity Engagement, Value-based Living, and Psychological Inflexibility
Abstract
Objective
This study examined symptom-based subgroups of metastatic breast cancer (MBC) patients and the extent to which they differed across key constructs of Acceptance and Commitment Therapy (ACT).
Methods
Eighty women with MBC completed self-report surveys assessing ten common symptoms and several ACT variables (i.e., activity engagement, psychological inflexibility, value obstruction, and value progress) during a single time point.
Results
A cluster analysis yielded three patient subgroups: low symptoms, low-moderate symptoms, and moderate-high symptoms. Relative to the subgroup with low symptoms, the other subgroups reported less activity engagement. In addition, compared to patients with low symptoms, the subgroup with moderate-high symptoms reported greater psychological inflexibility (i.e., avoidance of unwanted internal experiences) and greater difficulty living consistently with their values.
Conclusions
Women with MBC show heterogeneity in their symptom profiles, and those with higher symptom burden are more likely to disengage from valued activities and avoid unwanted experiences (e.g., thoughts, feelings, bodily sensations). Findings are largely consistent with the ACT model and provide strong justification for testing ACT to address symptom interference in MBC patients.
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Factors Associated with Oncology Patients’ Involvement in Shared Decision-Making During Chemotherapy
Abstract
Objective
Oncology patients are increasingly encouraged to play an active role in treatment decision-making. While previous studies have evaluated relationships between demographic characteristics and decision-making roles, less is known about the association of symptoms and psychological adjustment characteristics (e.g., coping styles, personality traits) and decision-making roles.
Methods
As part of a larger study of symptom clusters, patients (n = 765) receiving chemotherapy (CTX) for breast, gastrointestinal, gynecological, or lung cancer provided information on demographic, clinical, symptom, and psychological adjustment characteristics. Patient-reported treatment decision-making roles (i.e., preferred role, and role actually played) were assessed using the Control Preferences Scale. Differences among patients, who were classified as passive, collaborative, or active, were evaluated using Chi square analyses and analyses of variance.
Results
Over half (56.3%) of the patients reported both that they preferred, and that they actually played, a collaborative role. Among those patients with concordant roles, those who were older, those with less education and lower income, and those who were less resilient were more likely to prefer a passive role. Several psychological adjustment characteristics were associated with decision-making role, including coping style, personality, and fatalism.
Conclusions
Oncology patients' preferences for involvement in treatment decision-making are associated with demographic characteristics as well as with symptoms and psychological adjustment characteristics, such as coping style and personality. These results reaffirm the complexities of predicting patients' preferences for involvement in decision-making. Further study is needed to determine if role or coping style may be influenced by interventions designed to teach adaptive coping skills.
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Primary breast cancer cell culture yields intra-tumor heterogeneous subpopulations expressing exclusive patterns of receptor tyrosine kinases
Abstract
Background
It has become evident that intra-tumor heterogeneity of breast cancer impact on several biological processes such as proliferation, migration, cell death and also might contribute to chemotherapy resistance. The expression of Receptor Tyrosine Kinases (RTKs) has not been analyzed in the context of intra-tumor heterogeneity in a primary breast cancer cell culture. Several subpopulations were isolated from the MBCDF (M serial-breast cancer ductal F line) primary breast cancer cells and were successfully maintained in culture and divided in two groups according to their morphology and RTKs expression pattern, and correlated with biological processes like proliferation, migration, anchorage-independent cell growth, and resistance to cytotoxic chemotherapy drugs and tyrosine kinase inhibitors (TKIs).
Methods
Subpopulations were isolated from MBCDF primary breast cancer cell culture by limiting dilution. RTKs and hormone receptors were examined by Western blot. Proliferation was measure by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT assay). Cell viability was evaluated by Crystal Violet. Migration was assessed using Boyden chambers. Anchorage-independent cell growth was evaluated by colony formation in soft agar.
Results
Several subpopulations were isolated from the MBCDF breast cancer cells that were divided into two groups according to their morphology. Analysis of RTKs expression pattern showed that HER1, HER3, c-Met and VEGFR2 were expressed exclusively in cells from group 1, but not in cells from group 2. PDGFR was expressed only in cells from group 2, but not in cells from group 1. HER2, HER4, c-Kit, IGF1-R were expressed in all subpopulations. Biological processes correlated with the RTKs expression pattern. Group 2 subpopulations present the highest rate of cell proliferation, migration and anchorage-independent cell growth. Analysis of susceptibility to chemotherapy drugs and TKIs showed that only Paclitaxel and Imatinib behaved differently between groups. Group 1-cells were resistant to both Paclitaxel and Imatinib.
Conclusions
We demonstrated that subpopulations from MBCDF primary cell culture could be divided into two groups according to their morphology and a RTKs excluding-expression pattern. The differences observed in RTKs expression correlate with the biological characteristics and chemoresistance of each group. These results suggest that intra-tumor heterogeneity contributes to generate groups of subpopulations with a more aggressive phenotype within the tumor.
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Microsurgical resection of vestibular schwannomas: complication avoidance
Abstract
Vestibular schwannoma (VS) surgery requires appropriate patient selection, meticulous microsurgical technique and optimal post-operative care. Focused radiation is an effective alternative for the treatment of smaller VSs. For VS surgery to remain a reasonable option, surgery must be performed with a limited number of complications. Complication rates for VS surgery have increased over the last decade. This is likely due to (1) decreased surgical volume and as a result decreased microsurgical experience, (2) larger tumors undergoing surgery while smaller tumors are reserved for radiation, and (3) surgery for previously radiated tumors resulting in more difficult anatomic dissection. Appropriate management of complications is paramount. Herein, we discuss complications related to VS microsurgery and methods of avoidance. Specifically, we discuss the most frequently encountered complications, intraoperative monitoring and finally, methods of addressing these complications. With meticulous microsurgical technique, careful intraoperative monitoring and vigilant perioperative care one will ensure optimal patient outcomes.
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Sensitive Detection of a Small Parathyroid Adenoma Using Fluorocholine PET/CT: A Case Report
Abstract
Primary hyperparathyroidism is caused by parathyroid adenoma in the majority of cases and diagnosis is usually made biochemically. Pre-surgical localization of parathyroid adenoma is essential to limit the extent of surgery and avoid missing them at ectopic sites. Anatomical and functional imaging are used for the localization, but may fail to identify the small and ectopic parathyroid adenoma. We present a case of small sized ectopic parathyroid adenoma at unusual location detected by F-18 fluorocholine (FCH) PET/CT, where other imaging modalities failed. The post-operative histopathology confirmed the diagnosis of ectopic parathyroid adenoma.
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Relation of comorbidities and patient navigation with the time to diagnostic resolution after abnormal cancer screening
BACKGROUND
Whether patient navigation improves outcomes for patients with comorbidities is unknown. The aims of this study were to determine the effect of comorbidities on the time to diagnostic resolution after an abnormal cancer screening test and to examine whether patient navigation improves the timeliness and likelihood of diagnostic resolution for patients with comorbidities in comparison with no navigation.
METHODS
A secondary analysis of comorbidity data collected by Patient Navigation Research Program sites using the Charlson Comorbidity Index (CCI) was conducted. The participants were 6,349 patients with abnormal breast, cervical, colon, or prostate cancer screening tests between 2007 and 2011. The intervention was patient navigation or usual care. The CCI data were highly skewed across projects and cancer sites, and the CCI scores were categorized as 0 (CCI score of 0 or no comorbidities identified; 76% of cases); 1 (CCI score of 1; 16% of cases), or 2 (CCI score ≥ 2; 8% of cases). Separate adjusted hazard ratios for each site and cancer type were obtained, and then they were pooled with a meta-analysis random effects methodology.
RESULTS
Patients with a CCI score ≥ 2 had delayed diagnostic resolution after an abnormal cancer screening test in comparison with those with no comorbidities. Patient navigation reduced delays in diagnostic resolution, with the greatest benefits seen for those with a CCI score ≥ 2.
CONCLUSIONS
Persons with a CCI score ≥ 2 experienced significant delays in timely diagnostic care in comparison with patients without comorbidities. Patient navigation was effective in reducing delays in diagnostic resolution among those with CCI scores > 1. Cancer 2016. © 2016 American Cancer Society.
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National patterns of care and predictors of neoadjuvant and concurrent chemotherapy use with definitive radiotherapy in the treatment of patients with oropharyngeal squamous cell carcinoma
BACKGROUND
To the authors' knowledge, the patterns of care for the radiotherapy-based treatment of patients with stage III to IVB oropharyngeal squamous cell carcinoma (OPSCC) are poorly defined. The objective of the current study was to characterize the use and predictors of chemotherapy with radiotherapy for this population using the National Cancer Database.
METHODS
Patients in the National Cancer Database with AJCC (American Joint Committee on Cancer) stage III to IV OPSCC who were treated with radiotherapy between 2003 and 2012 were eligible for analysis. Treatment was defined as radiotherapy alone, concurrent chemoradiotherapy, or induction chemotherapy (IC). Multivariable regression with multilevel modeling was used to determine predictors of any chemotherapy use and, among patients receiving chemotherapy, the predictors of IC.
RESULTS
The majority (90%) of the 30,875 eligible patients received chemotherapy, the majority of whom (71% of the total) were treated with definitive chemoradiotherapy; a sizeable percentage of patients received IC (19% of total). On multivariable regression, younger age, favorable comorbidity status, and more advanced tumor and lymph node disease were found to be independent predictors of any chemotherapy and IC use. Nonwhite patients (odds ratio [OR], 0.71; P<.0001), women (OR, 0.74; P<.0001), and individuals without private insurance were found to be significantly less likely to receive chemotherapy. Patients treated at higher-volume institutions were significantly less likely to receive IC (OR, 0.69; P = .0006). Human papillomavirus status did not appear to independently influence treatment choice.
CONCLUSIONS
The vast majority of patients with stage III to IVB OPSCC who were treated with definitive radiotherapy received chemotherapy, which is consistent with high-level data and national recommendations. However, disparities with regard to race, sex, and insurance status emerged thereby requiring additional investigation. The frequent use of IC despite limited supportive evidence warrants research on physician and patient decision making and presents an opportunity to improve evidence-based treatment delivery. Cancer 2016. © 2016 American Cancer Society.
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A phase 2 study of dalantercept, an activin receptor-like kinase-1 ligand trap, in patients with recurrent or metastatic squamous cell carcinoma of the head and neck
BACKGROUND
Patients with platinum-refractory, recurrent or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN) have limited options. Activin receptor-like kinase 1 (ALK1) is a type I receptor of the transforming growth factor β superfamily expressed on activated endothelial cells. Dalantercept is an ALK1 receptor fusion protein that acts as a ligand trap to block signaling through ALK1 and inhibits stages of angiogenesis involved in blood vessel maturation and stabilization. In a phase 1 study, dalantercept demonstrated clinical activity in patients with RM-SCCHN. The objective of the current study was sought to evaluate the activity of dalantercept in RM-SCCHN.
METHODS
Forty-six patients received dalantercept at doses of 80 mg (n = 2), 0.6 mg/kg (n = 13), or 1.2 mg/kg (n = 31) subcutaneously every 3 weeks. The primary endpoint was the overall response rate according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Secondary endpoints included progression-free survival and overall survival, safety and tolerability, and pharmacokinetic and pharmacodynamic assessments.
RESULTS
Forty patients were evaluable for response (13 who received dalantercept 0.6 mg/kg and 27 who received dalantercept 1.2 mg/kg). The overall response rate was 5% (n = 2), and 35% of patients had stable disease; 44% of patients who received 1.2 mg/kg and 30.8% of those who received 0.6 mg/kg achieved disease control (partial response or stable disease). The median progression-fee survival was 1.4 months (95% confidence interval, 1.3-2.2 months), and the median overall survival was 7.1 months (95% confidence interval, 5.5-11.1 months). Drug-related adverse events (>15%) were anemia, fatigue, peripheral edema, headache, and hyponatremia.
CONCLUSIONS
In an unselected, heavily pretreated population of patients with RM-SCCHN, dalantercept monotherapy resulted in a favorable safety profile but only modest dose-dependent activity, and it did not meet the primary efficacy objective of the study. Cancer 2016. © 2016 American Cancer Society.
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Enzalutamide in castration-resistant prostate cancer patients with visceral disease in the liver and/or lung: Outcomes from the randomized controlled phase 3 AFFIRM trial
BACKGROUND
Patients with metastatic castration-resistant prostate cancer (mCRPC) and visceral metastases have a worse prognosis than those with nonvisceral metastases. Treatment with the androgen receptor inhibitor enzalutamide in the phase 3 AFFIRM trial led to significant improvements in outcomes for patients with mCRPC. For the current report, the authors analyzed the efficacy of enzalutamide among patients from the AFFIRM trial who had visceral disease.
METHODS
Patients who had liver and/or lung metastases at baseline were selected for prespecified overall survival (OS) and exploratory post hoc analyses, including prostate-specific antigen (PSA) response and the time to PSA and radiographic progression.
RESULTS
In patients who had liver metastases (n = 92), enzalutamide was associated with a lower risk of radiographic progression (hazard ratio [HR], 0.645; 95% confidence interval [CI], 0.413-1.008), improved 12-month OS (37.7% vs 20.6%) and radiographic progression-free survival (rPFS) (11.6% vs 3.0%) rates, and higher PSA response rates (35.1% vs 4.8%) compared with placebo. Enzalutamide-treated patients who had lung metastases (n = 104) had improved median OS (HR, 0.848; 95% CI, 0.510-1.410), a substantially reduced risk of radiographic progression (HR, 0.386; 95% CI, 0.259-0.577), improved 12-month OS (65.1% vs 55.3%) and rPFS (30.9% vs 8.2%) rates, increased time to PSA progression (HR, 0.358; 95% CI, 0.204-0.627), and a better PSA response rate (52.1% vs 4.9%) compared with those who received placebo. No increase in treatment-related adverse events was observed for the visceral metastases cohort compared with the nonvisceral metastases cohort.
CONCLUSIONS
Across multiple endpoints, patients who have visceral metastases have better outcomes with enzalutamide than with placebo. Cancer 2016. © 2016 American Cancer Society.
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Antiangiogenic agents in head and neck squamous cell carcinoma: Tired of going solo
Antiangiogenic therapies as single agents have failed to demonstrate significant antitumor activity in heavily pretreated, unselected populations with recurrent/metastatic head and neck squamous cell carcinoma. Much work is needed to evaluate rational strategies for combining antiangiogenic agents with other systemic therapies or with radiotherapy for head and neck squamous cell carcinoma to move the field forward. See also pages 000-000.
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Whole-exome sequencing and targeted gene sequencing provide insights into the role of PALB2 as a male breast cancer susceptibility gene
BACKGROUND
Male breast cancer (MBC) is a rare disease whose etiology appears to be largely associated with genetic factors. BRCA1 and BRCA2 mutations account for about 10% of all MBC cases. Thus, a fraction of MBC cases are expected to be due to genetic factors not yet identified. To further explain the genetic susceptibility for MBC, whole-exome sequencing (WES) and targeted gene sequencing were applied to high-risk, BRCA1/2 mutation–negative MBC cases.
METHODS
Germ-line DNA of 1 male and 2 female BRCA1/2 mutation–negative breast cancer (BC) cases from a pedigree showing a first-degree family history of MBC was analyzed with WES. Targeted gene sequencing for the validation of WES results was performed for 48 high-risk, BRCA1/2 mutation–negative MBC cases from an Italian multicenter study of MBC. A case-control series of 433 BRCA1/2 mutation–negative MBC and female breast cancer (FBC) cases and 849 male and female controls was included in the study.
RESULTS
WES in the family identified the partner and localizer of BRCA2 (PALB2) c.419delA truncating mutation carried by the proband, her father, and her paternal uncle (all affected with BC) and the N-acetyltransferase 1 (NAT1) c.97C>T nonsense mutation carried by the proband's maternal aunt. Targeted PALB2 sequencing detected the c.1984A>T nonsense mutation in 1 of the 48 BRCA1/2 mutation–negative MBC cases. NAT1 c.97C>T was not found in the case-control series.
CONCLUSIONS
These results add strength to the evidence showing that PALB2 is involved in BC risk for both sexes and indicate that consideration should be given to clinical testing of PALB2 for BRCA1/2 mutation–negative families with multiple MBC and FBC cases. Cancer 2016. © 2016 American Cancer Society.
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Cancer Fatalism and Preferred Sources of Cancer Information: an Assessment Using 2012 HINTS Data
Abstract
Cancer fatalism is associated with lower participation in cancer screening, nonadherence to cancer screening guidelines, and avoidance of medical care. Few studies, however, have examined the relationship between cancer fatalism and health information seeking. The purpose of this study was to examine the relationship between endorsement of fatalistic beliefs regarding cancer and preferred sources of cancer information. We analyzed data from the Health Information National Trends Survey 4 Cycle 2, which were collected in late 2012 and early 2013 (N = 3630). When weighted, the data are representative of the non-institutionalized US population aged 18 or older. In bivariate and multivariate analyses, we assessed three cancer fatalism beliefs as predictors of preferred use of healthcare provider versus preferred use of the Internet for cancer information. Results indicate the majority of US adults endorse one or more fatalistic beliefs about cancer. Unadjusted results indicate endorsing the fatalistic belief that "there's not much you can do to lower your chances of getting cancer" was significantly associated with lower odds of preferring the Internet (versus healthcare providers) as the source of cancer information (OR: 0.70; CI: 0.50, 0.98). In the adjusted model, however, none of the three cancer fatalism measures were significantly associated with preferred source of cancer information. In conclusion, fatalistic beliefs about cancer are common, and further research is warranted to understand cancer fatalism and whether and how it may impact health information-seeking behaviors.
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Current management and future directions in metastatic pancreatic adenocarcinoma
Of the anticipated 50,000 individuals expected to be diagnosed with pancreatic cancer in 2016, the majority will have metastatic disease. Given the noncurative nature of advanced pancreatic adenocarcinoma, treatment is aimed at inducing disease regression, controlling symptom, and extending life. The last 5 years have been marked by advances in the treatment of metastatic pancreatic cancer, specifically the approval by the US Food and Drug Administration of 2 combination chemotherapy regimens and the widespread use of a third, which have reproducibly been shown to improve survival. Ongoing studies are building on these regimens along with targeted and immunotherapeutic agents. This article will review the current treatment standards and emerging targets for metastatic pancreatic cancer. Cancer 2016. © 2016 American Cancer Society.
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Immunotherapy for prostate cancer: False promises or true hope?
Prostate cancer is the most commonly diagnosed cancer, and the second leading cause of cancer-related death for men in the United States. Despite the approval of several new agents for advanced disease, each of these has prolonged survival by only a few months. Consequently, new therapies are sorely needed. For other cancer types, immunotherapy has demonstrated dramatic and durable treatment responses, causing many to hope that immunotherapies might provide an ideal treatment approach for patients with advanced prostate cancer. However, apart from sipuleucel-T, prostate cancer has been conspicuously absent from the list of malignancies for which immunotherapies have received recent approval from the US Food and Drug Administration. This has left some wondering whether immunotherapy will "work" for this disease. In this review, the authors describe current developments in immunotherapy, including approaches to engage tumor-targeting T cells, disrupt immune regulation, and alter the immunosuppressive tumor microenvironment. The authors then describe the recent application of these approaches to the treatment of prostate cancer. Given the Food and Drug Administration approval of 1 agent, and the finding that several others are in advanced stages of clinical testing, the authors believe that immunotherapies offer real hope to improve patient outcomes for men with prostate cancer, especially as investigators begin to explore rational combinations of immunotherapies and combine these therapies with other conventional therapies. Cancer 2016. © 2016 American Cancer Society.
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The psychosocial experiences of women with breast cancer across the lifespan: A systematic review
Abstract
Objective
To summarize the psychosocial experience of women with breast cancer from a lifespan perspective by examining the findings of qualitative studies.
Methods
A meta-aggregate review of 24 qualitative studies was undertaken. To be included, studies must include women with a breast cancer diagnosis and focus on younger or older women (as defined by the study), or compare a psychosocial issue across the lifespan. Eight databases were searched systematically.
Results
Study participants ranged in age from 26 to 91 years. Sixteen studies focused on younger women, six focused on older women, and two included women across the lifespan. A total of 155 findings were extracted from the studies, and were aggregated into 11 categories. These were synthesized into four synthesized findings: 1) dealing with cancer, 2) the importance of caring, 3) the aftermath of cancer, and 4) fertility and infertility.
Conclusions
Further research is required to explore these findings, and to examine the needs of older women in particular. Delineating the similarities and differences in the needs of women across the lifespan will inform the development of psychosocial interventions for all women with breast cancer.
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Next-generation sequencing adds value to the preoperative diagnosis of pancreatic cysts
BACKGROUND
The diagnosis of a pancreatic cyst as mucinous or high-risk dictates the need for follow-up or surgery. Molecular analysis of aspirated pancreatic cyst fluid (PCF) can provide valuable information not obtained by carcinoembryonic antigen (CEA) analysis or cytology.
METHODS
All patients who underwent molecular analysis of PCF between March 2013 and June 2015 were reviewed, including pathology, imaging, and follow-up. Molecular testing was performed using a patented, anchored multiplex polymerase chain reaction next-generation sequencing (NGS) platform, which sequenced numerous hotspots in 39 genes linked with malignancy. Performance of NGS and cytology was calculated using final outcome, as determined by clinicopathologic follow-up.
RESULTS
The study cohort included 113 PCFs from 105 patients. In total, 119 variants were detected in 67 PCFs (59%). Variants were more common in intraductal papillary mucinous neoplasms (IPMNs)/cancer than in nonmucinous cysts (P < .005). The inclusion of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS)/guanine nucleotide-binding protein (GNAS) variants improved the classification of IPMNs as mucinous from 50% by microscopy to 100%. Seventy-five percent of cancers had high-grade atypia versus 0% of IPMNs and nonmucinous cysts (P < .002). Variants in tumor protein 53 (TP53), SMAD family member 4 (SMAD4), cyclin-dependent kinase inhibitor 2A (CDKN2A), and notch1 (NOTCH1) were detected only in malignant cysts. Cytology was similarly specific (100%) for detecting malignant cysts but was more sensitive than the identification of late mutations by NGS (75% vs 46%).
CONCLUSIONS
The detection of KRAS/GNAS variants improves the identification of mucinous neoplasms. Variants in TP53, SMAD4, CDKN2A, and NOTCH1 support the diagnosis of a high-risk cyst requiring surgery or additional sampling. Although molecular analysis is not a replacement for cytopathology, it does provide valuable information for accurate preoperative diagnosis, helping to classify mucinous neoplasms and high-risk cysts that require surgical resection. Cancer Cytopathol 2016. © 2016 American Cancer Society.
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Robotic gastrectomy versus open gastrectomy in the treatment of gastric cancer
Abstract
Background
Robotic gastrectomy (RG) has been developed to improve surgical quality and to overcome the limitations of conventional open gastrectomy (OG) for gastric cancer. The aim of this meta-analysis is to comprehensively compare the safety and efficacy between robotic surgery and open surgery for treating gastric cancer.
Methods
Major databases were searched for retrospective case-matched studies comparing RG and OG for treating gastric cancer. A list of these studies, published in English from 1990 to 2016, was obtained independently by two reviewers from databases such as PubMed, MEDLINE, ScienceDirect, the China National Knowledge Infrastructure and Web of Science. Intraoperative data, oncological outcomes and postoperative complications were compared using Review Manager 5.3.
Results
Seven studies involving 5970 patients with 606 cases of RG and 5364 cases of OG were included in this meta-analysis. Compared to OG, RG has a significantly longer operation time [weighted mean differences (WMD) = 63.72, 95 % confidence interval (CI) 33.83–93.61, P < 0.0001], lower blood loss (WMD: −129.74, 95 % CI −178.31 to −81.16, P < 0.00001) and shorter hospital stay (WMD = −2.39, 95 % CI −2.92 to −1.87; P < 0.00001). No statistical difference was noted based on the rate of overall postoperative complication, wound infection, bleeding, ileus and obstruction, abdominal collections and abscesses, and the rate of anastomotic leak in the RG versus OG. Postoperative oncological outcomes showed that there were also no statistical differences among the number of retrieved lymph nodes, proximal resection margin, distal resection margin except for tumor size (WMD = −1.60; 95 % CI −2.96 to −0.25; P = 0.02).
Conclusion
The results of this meta-analysis suggest that RG will be more accessible than conventional OG for gastric cancer. However, more prospective, well-designed, multicenter, randomized controlled trials are necessary to further evaluate the safety and efficacy as well as the long-term outcome of this technology.
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A long non-coding RNA signature to improve prognosis prediction of gastric cancer
Abstract
Background
Increasing evidence suggests long non-coding RNAs (lncRNAs) are frequently aberrantly expressed in cancers, however, few related lncRNA signatures have been established for prediction of cancer prognosis. We aimed at developing alncRNA signature to improve prognosis prediction of gastric cancer (GC).
Methods
Using a lncRNA-mining approach, we performed lncRNA expression profiling in large GC cohorts from Gene Expression Ominus (GEO), including GSE62254 data set (N = 300) and GSE15459 data set (N = 192). We established a set of 24-lncRNAs that were significantly associated with the disease free survival (DFS) in the test series.
Results
Based on this 24-lncRNA signature, the test series patients could be classified into high-risk or low-risk subgroup with significantly different DFS (HR = 1.19, 95 % CI = 1.13–1.25, P < 0.0001). The prognostic value of this 24-lncRNA signature was confirmed in the internal validation series and another external validation series, respectively. Further analysis revealed that the prognostic value of this signature was independent of lymph node ratio (LNR) and postoperative chemotherapy. Gene set enrichment analysis (GSEA) indicated that high risk score group was associated with several cancer recurrence and metastasis associated pathways.
Conclusions
The identification of the prognostic lncRNAs indicates the potential roles of lncRNAs in GC biogenesis. Our results may provide an efficient classification tool for clinical prognosis evaluation of GC.
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Quantification of myocardial blood flow with 82 Rb: Validation with 15 O-water using time-of-flight and point-spread-function modeling
Abstract
Background
We quantified myocardial blood flow with 82Rb PET using parameters of the generalized Renkin-Crone model estimated from 82Rb and 15O-water images reconstructed with time-of-flight and point spread function modeling. Previous estimates of rubidium extraction have used older-generation scanners without time-of-flight or point spread function modeling. We validated image-derived input functions with continuously collected arterial samples.
Methods
Nine healthy subjects were scanned at rest and under pharmacological stress on the Siemens Biograph mCT with 82Rb and 15O-water PET, undergoing arterial blood sampling with each scan. Image-derived input functions were estimated from the left ventricle cavity and corrected with tracer-specific population-based scale factors determined from arterial data. Kinetic parametric images were generated from the dynamic PET images by fitting the one-tissue compartment model to each voxel's time activity curve. Mean myocardial blood flow was determined from each subject's 15O-water k 2 images. The parameters of the generalized Renkin-Crone model were estimated from these water-based flows and mean myocardial 82Rb K 1 estimates.
Results
Image-derived input functions showed improved agreement with arterial measurements after a scale correction. The Renkin-Crone model fit (a = 0.77, b = 0.39) was similar to those previously published, though b was lower.
Conclusions
We have presented parameter estimates for the generalized Renkin-Crone model of extraction for 82Rb PET using human 82Rb and 15O-water PET from high-resolution images using a state-of-the-art time-of-flight-capable scanner. These results provide a state-of-the-art methodology for myocardial blood flow measurement with 82Rb PET.
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Cancers, Vol. 8, Pages 86: Technical Considerations for the Generation of Adoptively Transferred T Cells in Cancer Immunotherapy
A significant function of the immune system is the surveillance and elimination of aberrant cells that give rise to cancer. Even when tumors are well established and metastatic, immune-mediated spontaneous regressions have been documented. While there are have been various forms of immunotherapy, one of the most widely studied for almost 40 years is adoptive cellular immunotherapy, but its success has yet to be fully realized. Adoptive cell transfer (ACT) is a therapeutic modality that has intrigued physicians and researchers for its many theoretical benefits. Preclinical investigations and human trials have utilized natural killer (NK) cells, dendritic cells (DC), macrophages, T-cells or B-cells for ACT with the most intense research focused on T-cell ACT. T-cells are exquisitely specific to the target of its T-cell receptor (TCR), thus potentially reducing the amount of collateral damage and off-target effects from treatment. T-cells also possess a memory subset that may reduce the risk of recurrence of a cancer after the successful treatment of the primary disease. There are several options for the source of T-cells used in the generation of cells for ACT. Perhaps the most widely known source is T-cells generated from tumor-infiltrating lymphocytes (TILs). However, studies have also employed peripheral blood mononuclear cells (PBMCs), lymph nodes, and even induced pluripotent stem cells (IPSCs) as a source of T-cells. Several important technical considerations exist regarding benefits and limitations of each source of T-cells. Unique aspects of T-cells factor into their ability to be efficacious in ACT including the total number of cells available for ACT, the anti-tumor efficacy on a per cell basis, the repertoire of TCRs specific to tumor cells, and their ability to traffic to various organs that harbor tumor. Current research is attempting to unlock the full potential of these cells to effectively and safely treat cancer.
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Cancer Fatalism and Preferred Sources of Cancer Information: an Assessment Using 2012 HINTS Data
Abstract
Cancer fatalism is associated with lower participation in cancer screening, nonadherence to cancer screening guidelines, and avoidance of medical care. Few studies, however, have examined the relationship between cancer fatalism and health information seeking. The purpose of this study was to examine the relationship between endorsement of fatalistic beliefs regarding cancer and preferred sources of cancer information. We analyzed data from the Health Information National Trends Survey 4 Cycle 2, which were collected in late 2012 and early 2013 (N = 3630). When weighted, the data are representative of the non-institutionalized US population aged 18 or older. In bivariate and multivariate analyses, we assessed three cancer fatalism beliefs as predictors of preferred use of healthcare provider versus preferred use of the Internet for cancer information. Results indicate the majority of US adults endorse one or more fatalistic beliefs about cancer. Unadjusted results indicate endorsing the fatalistic belief that "there's not much you can do to lower your chances of getting cancer" was significantly associated with lower odds of preferring the Internet (versus healthcare providers) as the source of cancer information (OR: 0.70; CI: 0.50, 0.98). In the adjusted model, however, none of the three cancer fatalism measures were significantly associated with preferred source of cancer information. In conclusion, fatalistic beliefs about cancer are common, and further research is warranted to understand cancer fatalism and whether and how it may impact health information-seeking behaviors.
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Message from Dr. Lowy
Dear Colleagues,
NCI's RAS Initiative has come a long way since 2013, when former NCI director Dr. Harold Varmus and a group of experts envisioned a coordinated effort to understand the biology of RAS oncogenes. At that time, drugging RAS was a goal that had been all but abandoned by industry and many academic researchers, after years of trying. Today's concerted effort, led by the RAS Initiative, is beginning to make headway.
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[High-dose chemotherapy as a strategy to overcome drug resistance in solid tumors].
[High-dose chemotherapy as a strategy to overcome drug resistance in solid tumors].
Bull Cancer. 2016 Sep 15;
Authors: Selle F, Gligorov J, Soares DG, Lotz JP
Abstract
The concept of high-doses chemotherapy was developed in the 1980s based on in vitro scientific observations. Exposure of tumor cells to increasing concentrations of alkylating agents resulted in increased cell death in a strong dose-response manner. Moreover, the acquired resistance of tumor cells could be overcome by dose intensification. In clinic, dose intensification of alkylating agents resulted in increased therapeutic responses, however associated with significant hematological toxicity. Following the development of autologous stem cells transplantation harvesting from peripheral blood, the high-doses of chemotherapy, initially associated with marked toxic effects, could be more easily tolerated. As a result, the approach was evaluated in different types of solid tumors, including breast, ovarian and germ cell tumors, small cell lung carcinoma, soft tissue sarcomas and Ewing sarcoma. To date, high-doses chemotherapy with hematopoietic stem cells support is only used as a salvage therapy to treat poor prognosis germ cell tumors patients with chemo-sensitive disease. Regarding breast and ovarian cancer, high-doses chemotherapy should be considered only in the context of clinical trials. However, intensive therapy as an approach to overcome resistance to standard treatments is still relevant. Numerous efforts are still ongoing to identify novel therapeutic combinations and active treatments to improve patients' responses.
PMID: 27641463 [PubMed - as supplied by publisher]
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[Osimertinib (Tagrisso(®)): Activity, indication and modality of use in non-small cell lung cancer].
[Osimertinib (Tagrisso(®)): Activity, indication and modality of use in non-small cell lung cancer].
Bull Cancer. 2016 Sep 15;
Authors: Giroux Leprieur E, Cortot AB, Cadranel J, Wislez M
Abstract
The acquisition of a resistance EGFR mutation in exon 20 (T790M) occurs in half of the cases of secondary resistance to EGFR tyrosine kinase inhibitors (TKI), given in first-line treatment in advanced EGFR-mutated non-small cell lung cancers (NSCLC). Osimertinib (AZD9291, Tagrisso(®)) is a third-generation, irreversible EGFR TKI, active in case of T790M mutation. A large phase I trial showed the efficacy of osimertinib after failure of first-generation EGFR TKI (erlotinib, gefitinib), with response rate at 51% and up to 61% in case of T790M mutation. Progression-free survival was 9.6 months in case of T790M. Toxicity profile was acceptable, with mainly digestive (diarrhea) and skin (rash) side effects. Preliminary data from a phase II trial confirmed these efficacy and safety data. Screening of T790M mutation at the time of progression with TKI can be performed in circulating tumor DNA in plasma, with good diagnostic performances.
PMID: 27641462 [PubMed - as supplied by publisher]
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Targeting Netrin-1 in glioblastoma stem-like cells inhibits growth, invasion, and angiogenesis
Abstract
Glioblastoma (GBM) is an aggressive malignant brain tumor that still lacks effective therapy. Glioblastoma stem cells (GBM-SCs) were identified to contribute to aggressive phenotypes and poor clinical outcomes for GBM. Netrin-1, an axon guidance molecule, has been found in several tumors in adults. However, the role of Netrin-1 in GBM-SCs remains largely unknown. In this study, CD133-positive U251 GBM cells were used as a putative GBM-SC population to identify the functions of Netrin-1. Using lentiviral transduction, Netrin-1 miR RNAi vectors were transduced into CD133-positive U251 cells. We demonstrated that cell proliferation and survival were decreased following targeted deletion of Netrin-1. Cell invasion was dramatically diminished in Netrin-1 knockdown GBM-SCs. Moreover, Netrin-1 knockdown GBM-SCs exhibited less proangiogenic activity. In conclusion, Netrin-1 may represent a therapeutic target in glioblastoma.
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The predictive potential and oncogenic effects of HOXC8 expression on osteosarcoma
Abstract
Homeobox C8 (HOXC8) has been implicated in cell growth, migration, and metastasis of various cancers, yet its role in osteosarcoma remains to be explored. In the present study, resected osteosarcoma specimens from 50 patients were enrolled to evaluate the expression of HOXC8 protein by immunohistochemistry (IHC). In vitro and in vivo assays were used to determine the effect of HOXC8 on cell growth, migration, and tumor growth. HOXC8 expression was observed in 31 (62.0 %) of the 50 primary tumors and significantly associated with poorly or un-differentiated specimens (P = 0.031) and larger tumor size (P = 0.049). Survival analysis demonstrated that HOXC8 is a candidate predictive factor in predicting patients' outcome and chemotherapeutic effect. HOXC8 knockdown led to inhibition of tumor cell proliferation and migration in vitro by inhibiting MMP-9 expression and tumor growth in vivo. Our results strongly suggest that HOXC8 is involved in the tumorigenesis of osteosarcoma and might serve as a novel predictor for patients' outcome.
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Breast cancer classification and prognostication through diverse systems along with recent emerging findings in this respect; the dawn of new perspectives in the clinical applications
Abstract
Breast cancer is the most common malignancy among women and the second leading cause of mortality due to cancer worldwide. The complexity of breast cancer resembles an intricate ecosystem comprising various cleverly designed interaction levels of internal and external factors to generate a pliable context in the clonal evolution of breast cancer cells. Principally, the complex entity can become evident toward delineating a number of significant variations in the specific fields of breast cancer analyses, including the molecular, physiological, and morphological characteristics, clinical presentations, risk factors, the histopathological conditions, and response to systemic therapy regarding the maintenance of tumor as a whole. In hindsight, various classification systems developing based on specific inclusion criteria have indisputably changed both our appreciation of the biological demeanor of breast cancer and the main strategies for designing tailored therapy regimens through the proper evaluation of diagnosis and prognostication of given specimens. Here, we endeavor to provide a general overview of different types of breast cancer classification as well as the clinical acceptance of their applications along with the latest findings in this area. Taken together, the major significance of breast cancer management that can be ascertained by operational convergent points of its stratification areas is owing to the fact that the achievement of individualized and targeted therapy may denounce new horizons of surveillance and treatment strategies in which they may function as a rheostat of specific therapy regimens toward reducing the detected distances between experimental data and operating options in clinical practice.
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Genotypic distribution of single nucleotide polymorphisms in oral cancer: global scene
Abstract
Globocan 2012 reports the global oral cancer incidence of 300,373 new oral cancer cases annually, contributing to 2.1 % of the world cancer burden. The major well-established risk factors for oral cancer include tobacco, betel/areca nut, alcohol and high-risk oncogenic human papilloma virus (HPV) 16/18. However, only 5–10 % of individuals with high-risk lifestyle develop oral cancer. Thus, genomic variants in individuals represented as single nucleotide polymorphisms (SNPs) influence susceptibility to oral cancer. With a view to understanding the role of genomic variants in oral cancer, we reviewed SNPs in case–control studies with a minimum of 100 cases and 100 controls. PubMed and HuGE navigator search engines were used to obtain data published from 1990 to 2015, which identified 67 articles investigating the role of SNPs in oral cancer. Single publications reported 93 SNPs in 55 genes, with 34 SNPs associated with a risk of oral cancer. Meta-analysis of data in multiple studies defined nine SNPs associated with a risk of oral cancer. The genes were associated with critical functions deregulated in cancers, including cell proliferation, immune function, inflammation, transcription, DNA repair and xenobiotic metabolism.
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Multiregion sequencing reveals the intratumor heterogeneity of driver mutations in TP53-driven non-small cell lung cancer
Abstract
Intratumor heterogeneity (ITH) in non-small cell lung cancer (NSCLC) may account for resistance after a period of targeted therapies because drugs destroy only a portion of tumor cells. The recognition of ITH helps identify high-risk patients to make effective treatment decisions. However, ITH studies are confounded by interpatient heterogeneity in NSCLC and a large amount of passenger mutations. To address these issues, we recruited NSCLC patients carrying TP53 mutations and selected driver mutations within recurrently mutated genes in NSCLC. A total of 12-paired normal-tumor tissues were subjected to whole-genome/whole-exome sequencing. From these, 367 non-silent mutations were selected as driver mutations and deeply sequenced in 61 intratumoral microdissections. We identified a universal prevalence of heterogeneity in all 12 tumors, indicating branched evolution. Although TP53 mutations were observed in single biopsy of all 12 tumors, most tumors consist of both TP53 mutated and non-mutated cells in separate regions within the same tumor. This suggests the late molecular timing of the acquisition of TP53 mutations; therefore, the detection of TP53 mutations in a single biopsy may simply not reflect the early malignant potential. Additionally, we identified regions of loss of heterozygosity surrounding TP53 and CDKN2A mutations in tumor 711, which also exhibited heterogeneity in different regional samples. Because the ITH of driver mutations likely has clinical consequences, further efforts are needed to limit the impact of ITH and to improve therapeutic efficiency, which will benefit NSCLC patients receiving targeted treatments. This article is protected by copyright. All rights reserved.
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