We have proposed that safe and effective protection against the development of adult onset cancers may be achieved by vaccination against tissue-specific self-proteins that are "retired" from expression at immunogenic levels in normal tissues as we age, but are overexpressed in emerging tumors. α-Lactalbumin is an example of a "retired" self-protein because its expression in normal tissues is confined exclusively to the breast during late pregnancy and lactation, but is also expressed in the vast majority of human triple negative breast cancers (TNBC)—the most aggressive and lethal form of breast cancer and the predominant form that occurs in women at high genetic risk including those with mutated BRCA1 genes. In anticipation of upcoming clinical trials, here we provide preclinical data indicating that α-lactalbumin has the potential as a vaccine target for inducing safe and effective primary immunoprevention as we
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Σάββατο 3 Σεπτεμβρίου 2016
Cancers, Vol. 8, Pages 56: Targeted Vaccination against Human α-Lactalbumin for Immunotherapy and Primary Immunoprevention of Triple Negative Breast Cancer
Identification of long noncoding RNAs as potential novel diagnosis and prognosis biomarkers in colorectal cancer
Abstract
Background
Colorectal cancer (CRC) is prevalent worldwide, and improvements in timely and effective diagnosis are imperatively needed. We aimed to identify potential long noncoding RNA (lncRNA) biomarkers for CRC diagnosis along with prognosis prediction.
Methods
LncRNA expression profiles were studied by microarray in paired tumor and normal tissues from six patients with CRC. The expression levels of candidate lncRNAs were analyzed in 80 pairs of tissues and two independent cohorts of serum samples. Receiver-operating characteristic (ROC) curves were employed to evaluate the performance of the lncRNAs identified. The correlation between lncRNAs and disease-specific survival rate of CRC patients was assessed to explore prognostic potential.
Results
Four lncRNAs (BANCR, NR_026817, NR_029373, and NR_034119) were identified to be significantly dysregulated in both tissue and serum samples with consistent pattern, and a panel was established based on this result. The performance of the 4-lncRNA panel was measured with an area under the ROC curve (AUC) of 0.881. The corresponding AUCs of the panel for patients with TNM stageI, II and III were 0.774, 0.844 and 0.949, respectively, significantly higher than that of CEA. Kaplan–Meier analysis showed that patients with low levels of NR_029373 and NR_034119 had significantly lower disease-specific survival rate (p = 0.013 and 0.044, respectively). Multivariate Cox analysis demonstrated that NR_029373 and NR_034119 were both independently associated with disease-specific survival rate (p = 0.013 and 0.038, respectively).
Conclusions
Our study established a distinctive 4-lncRNA panel with considerable diagnostic value and identified NR_029373 and NR_034119 as potential biomarkers for CRC prognosis prediction.
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Armillaridin induces autophagy-associated cell death in human chronic myelogenous leukemia K562 cells
Abstract
Armillaridin (AM) is an aromatic ester compound isolated from Armillaria mellea. Treatment with AM markedly reduced the viability of human chronic myelogenous leukemia K562, chronic erythroleukemia HEL 92.1.7, and acute monoblastic leukemia U937 cells, but not normal human monocytes, in a dose- and time-dependent manner. Treatment of K562 cells with AM caused changes characteristic of autophagy. Only a small amount of AM-treated K562 cells exhibited apoptosis. By contrast, AM treatment resulted in extensive apoptotic features in U937 and HEL 92.1.7 cells without evident autophagy. The autophagy of K562 cells induced by AM involved autophagic flux, including autophagosome induction, the processing of autophagosome-lysosome fusion and downregulation of BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3). By bcr-abl knockdown, the growth inhibition of K562 cells caused by AM was partially blocked, suggesting that AM-induced cell death might be a bcr-abl-dependent mode of autophagy-associated cell death. In conclusion, AM is capable of inhibiting growth and inducing autophagy-associated cell death in K562 cells, but not in normal monocytes. It may have potential to be developed as a novel therapeutic agent against leukemia.
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Myopodin methylation is a prognostic biomarker and predicts antiangiogenic response in advanced kidney cancer
Abstract
Myopodin is a cytoskeleton protein that shuttles to the nucleus depending on the cellular differentiation and stress. It has shown tumor suppressor functions. Myopodin methylation status was useful for staging bladder and colon tumors and predicting clinical outcome. To our knowledge, myopodin has not been tested in kidney cancer to date. The purpose of this study was to evaluate whether myopodin methylation status could be clinically useful in renal cancer (1) as a prognostic biomarker and 2) as a predictive factor of response to antiangiogenic therapy in patients with metastatic disease. Methylation-specific polymerase chain reactions (MS-PCR) were used to evaluate myopodin methylation in 88 kidney tumors. These belonged to patients with localized disease and no evidence of disease during follow-up (n = 25) (group 1), and 63 patients under antiangiogenic therapy (sunitinib, sorafenib, pazopanib, and temsirolimus), from which group 2 had non-metastatic disease at diagnosis (n = 32), and group 3 showed metastatic disease at diagnosis (n = 31). Univariate and multivariate Cox analyses were utilized to assess outcome and response to antiangiogenic agents taking progression, disease-specific survival, and overall survival as clinical endpoints. Myopodin was methylated in 50 out of the 88 kidney tumors (56.8 %). Among the 88 cases analyzed, 10 of them recurred (11.4 %), 51 progressed (57.9 %), and 40 died of disease (45.4 %). Myopodin methylation status correlated to MSKCC Risk score (p = 0.050) and the presence of distant metastasis (p = 0.039). Taking all patients, an unmethylated myopodin identified patients with shorter progression-free survival, disease-specific survival, and overall survival. Using also in univariate and multivariate models, an unmethylated myopodin predicted response to antiangiogenic therapy (groups 2 and 3) using progression-free survival, disease-specific, and overall survival as clinical endpoints. Myopodin was revealed hypermethylated in kidney cancer. Myopodin methylation status identified which patients showed a more aggressive clinical behavior and predicted antiangiogenic response. These observations support the clinical utility of an unmethylated myopodin as a prognostic and predictive biomarker in kidney cancer.
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Utah Cancer Survivors: A Comprehensive Comparison of Health-Related Outcomes Between Survivors and Individuals Without a History of Cancer
Abstract
Assessments of cancer survivors' health-related needs are often limited to national estimates. State-specific information is vital to inform state comprehensive cancer control efforts developed to support patients and providers. We investigated demographics, health status/quality of life, health behaviors, and health care characteristics of long-term Utah cancer survivors compared to Utahans without a history of cancer. Utah Behavioral Risk Factor Surveillance System (BRFSS) 2009 and 2010 data were used. Individuals diagnosed with cancer within the past 5 years were excluded. Multivariable survey weighted logistic regressions and computed predictive marginals were used to estimate age-adjusted percentages and 95 % confidence intervals (CI). A total of 11,320 eligible individuals (727 cancer survivors, 10,593 controls) were included. Respondents were primarily non-Hispanic White (95.3 % of survivors, 84.1 % of controls). Survivors were older (85 % of survivors ≥40 years of age vs. 47 % of controls). Survivors reported the majority of their cancer survivorship care was managed by primary care physicians or non-cancer specialists (93.5 %, 95 % CI = 87.9–99.1). Furthermore, 71.1 % (95 % CI = 59.2–82.9) of survivors reported that they did not receive a cancer treatment summary. In multivariable estimates, fair/poor general health was more common among survivors compared to controls (17.8 %, 95 % CI = 12.5–23.1 vs. 14.2 %, 95 % CI = 12.4–16.0). Few survivors in Utah receive follow-up care from a cancer specialist. Provider educational efforts are needed to promote knowledge of cancer survivor issues. Efforts should be made to improve continuity in follow-up care that addresses the known issues of long-term survivors that preclude optimal quality of life, resulting in a patient-centered approach to survivorship.
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The limitations of opportunistic epidemiology, pseudopod epidemiology
Abstract
Epidemiology has been remarkably successful in the past in identifying the important agents of disease, the impact of the environment, both physical and social, and interrelationship with host susceptibility (genomics). Many of the advances in improving the health of individuals and populations have been the result of epidemiology studies that have identified the specific "agents" of disease and application of public health and preventive medicine. In recent years, large longitudinal studies have dominated epidemiology research, especially long incubation period chronic diseases. The initial hypotheses in these studies have been expanded by vertical extension studies using newer technologies to measure independent variables, vertical pseudopods, and additional studies of other diseases, horizontal pseudopods, of the original longitudinal study. Host susceptibility, i.e. genomics, has also become a prominent component of these longitudinal studies. The critical question addressed in this paper is whether these "pseudopod" epidemiology approaches have enhanced public health or generated a large number of studies of little impact.
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Long term update of Trial ****: A Phase I/II Trial to Evaluate Three Dimensional Conformal Radiation Therapy (3D-CRT) Confined to the Region of the Lumpectomy Cavity for Stage I and II Breast Carcinoma
Publication date: Available online 3 September 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Rachel Rabinovitch, Jennifer Moughan, Frank Vicini, Helen Pass, John Wong, Susan Chafe, Ivy Petersen, Douglas W. Arthur, Julia White
PurposeTrial **** was the first cooperative group trial in the US to evaluate 3-dimensional conformal radiation therapy (3D-CRT) accelerated partial breast irradiation (APBI). This report updates secondary endpoints of toxicity and efficacy.MethodsPatients (pts) with stage I/II invasive breast cancer (BrCa) (T≤3cm, N≤3 positive lymph nodes, negative margins) were eligible for 3D-CRT APBI - 38.5 Gy in 10 BID fractions. Pt characteristics and treatment details have previously been reported. Adverse Events (AEs) were graded with CTCAE v. 3.0. This analysis updates recurrences in the ipsilateral breast (IBR), contralateral breast (CBR), ipsilateral nodes (INR), and metastatic sites (DM), mastectomy rate (M), disease-free (DFS), mastectomy-free (MFS), and overall survival (OS).Results52 of 58 enrolled pts were eligible: median age 61 years (y), 94% stage I and 83% ER positive. Median follow up is 8y (min-max: 1.7 – 9.0). The 7y estimate of isolated IBR (no DM) is 5.9%. 7y estimates of all IBR, INR, M, and DM were 7.7%, 5.8%, 7.7%, and 7.7%, respectively. All 4 IBRs were invasive of which 3 had a component within the planning target volume. Patterns of failures were: 3 IBR, 1 INR, 2 DM, 1 INR+DM, and 1 IBR+INR+DM. 7y estimates of MFS, DFS, and OS are 71.2%, 71.2%, and 78.8%, respectively. 13 pts have died: 3 of BrCa, 10 of other causes. Four pts (7.7%) reported G3 treatment-related AE. No G3 pain, pulmonary, or cardiac toxicities were reported.ConclusionThis phase I/II trial of 3D-CRT APBI continues to demonstrate durable tumor control and minimal G3 toxicity, comparable to other APBI techniques. Mature phase III results will determine the appropriateness and limitations of this non-invasive APBI technique.
Teaser
Updated follow up of patients treated with 3D-conformal accelerated partial breast irradiation on Trial **** demonstrates durable ipsilateral breast tumor control and minimal grade 3 toxicity at 7 years, comparable to other published prospective APBI trials. No G3 pain, pulmonary, or cardiac toxicities were reported. Mature phase III results from pending randomized trials utilizing this non-invasive treatment technique are awaited to fully assess its role in early stage breast cancer management.from Cancer via ola Kala on Inoreader http://ift.tt/2cnQMcM
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Salvage Radiotherapy Dose Response for Biochemical Failure of Prostate Cancer after Prostatectomy - A Multi-Institutional Observational Study
Publication date: Available online 3 September 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Thomas M. Pisansky, Shree Agrawal, Daniel A. Hamstra, Bridget F. Koontz, Stanley L. Liauw, Jason A. Efstathiou, Jeff M. Michalski, Felix Y. Feng, Matthew C. Abramowitz, Alan Pollack, Mitchell S. Anscher, Drew Moghanaki, Robert B. Den, Kevin L. Stephans, Anthony L. Zietman, W. Robert Lee, Michael W. Kattan, Andrew J. Stephenson, Rahul D. Tendulkar
Ten academic centers in the United States pooled individual prostate cancer patient data into a centralized database in order to describe the effects of salvage radiotherapy for detectable serum prostate-specific antigen after prostatectomy. The outcomes of 1108 such patients are presented, focusing on the relationship of radiotherapy dose with selected endpoints. The incidence of biochemical failure after radiotherapy was reduced when ≥66.0 Gy was prescribed, supporting higher-dose salvage radiotherapy whenever feasible.
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A novel respiratory motion perturbation model adaptable to patient breathing irregularities
Publication date: Available online 3 September 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Amy Yuan, Jie Wei, Carl P. Gaebler, Hailiang Huang, Devin Olek, Guang Li
PurposeTo develop a physical, adaptive motion perturbation model to predict tumor motion using feedback from dynamic measurement of breathing conditions to compensate for breathing irregularities.Methods and MaterialsA novel respiratory motion perturbation (RMP) model was developed to predict tumor motion variations caused by breathing irregularities. This model contained two terms: initial tumor motion trajectory (MT) measured from four-dimensional computed tomography (4DCT) and motion perturbation (ΔMT), calculated from breathing variations in tidal volume (TV) and breathing pattern (BP). The ΔMT was derived from patient-specific anatomy, tumor-specific location, and time-dependent breathing variations. Ten patients were studied and two amplitude-binned 4DCT images for each patient were acquired within two weeks. The motion trajectories of 40 corresponding bifurcation points in both 4DCT images of each patient were obtained using deformable image registration. An in-house 4D data processing toolbox was developed to calculate TV and BP as functions of the breathing phase. The motion was predicted from 4DCTsim to 4DCTtxt, and vice versa, resulting in a total of 800 predictions. As comparisons, non-corrected (NC) motion differences and the predictions from a published 5D model were used.ResultsThe average motion range in the superior-inferior direction was 9.4±4.4mm, while an average ΔTV ranged 10-248 mm3 (-26–61%), and ΔBP ranged 0-0.2 (-71-333%) between two 4DCT. The mean NC motion difference was 2.0±2.8mm between two 4DCT MTs. After applying the RMP model, the mean motion difference was reduced significantly to 1.2±1.8 mm (p=0.0018), a 40% improvement, similar to 1.2±1.8 mm (p=0.72) predicted with the 5D model.ConclusionA novel physical RMP model was developed with average accuracy of 1.2±1.8 mm for interfractional motion prediction, similar to that of a published lung motion model. This physical RMP is analytically derived and able to adapt to breathing irregularities. Further improvement of this RMP model is under investigation.
Teaser
ovel physics-law-based respiratory motion perturbation model is developed to predict tumor motion under breathing irregularities. This adaptive model predicts motion variations using tidal-volume and breathing-pattern updates and is validated using two 4DCT sets from ten patients. Forty motion trajectories of 40 bifurcation points per 4DCT are tracked and 800 4DCT1↔4DCT2 predictions are evaluated with known ground truth. Average accuracy (1.2±1.8mm) is achieved, similar to an established model while significantly improved from raw motion differences.from Cancer via ola Kala on Inoreader http://ift.tt/2cnRGWD
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Multi-center Phase II Study of Cisplatin and 5-FU with Concurrent Radiotherapy as an Organ Preservation Approach in Patients with Squamous Cell Carcinoma of the Cervical Esophagus
Publication date: Available online 3 September 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Sadamoto Zenda, Takashi Kojima, Ken Kato, Sachiko Izumi, Taijiro Ozawa, Naomi Kiyota, Chikatoshi Katada, Takahiro Tsushima, Yoshinori Ito, Tetsuo Akimoto, Yasuhisa Hasegawa, Miyuki Kanamaru, Hiroyuki Daiko
ObjectiveWe conducted a multi-center single-arm phase II study to clarify the clinical profile of chemoradiotherapy for cervical esophageal cancer. (UMIN-CTR: UMIN000001439).BackgroundChemoradiotherapy for cervical esophageal cancer has not been prospectively evaluated, limiting information on the clinical profile of this treatment.MethodsPatients with operable cervical esophageal cancer, excluding candidates for endoscopic resection, were enrolled. Protocol treatment consisted of CRT and adjuvant chemotherapy. First, patients received concurrent CRT with 5-FU plus CDDP. Chemotherapy consisted of 5-FU at 700 mg/m2 i.v. on days 1-4 and CDDP at 70 mg/m2 on day 1 i.v., repeated every 4 weeks for two cycles. Radiation therapy consisted of 60 Gy in 30 fractions. After completion of CRT, two additional cycles of chemotherapy with 5-FU (800 mg/m2, days 1-5) and CDDP (80 mg/m2, day 1) were repeated at a 4-week interval. Primary endpoint was 3-year overall survival.ResultsThirty patients were enrolled across eight institutions in Japan, consisting of 26 males and 4 females with a median age of 64.5 years (range 50–75). No grade 4 hematologic toxicity was seen in the CRT phase and one grade 4 thrombocytopenia was seen in the CT phase. Grade 3 non-hematologic acute toxicities in the CRT phase were nausea (10%), mucositis (13.3%), and dysphagia (13.3%). No treatment-related death in both phase occurred. Overall complete response rate was 73% and 3-year overall and laryngectomy-free survival were 66.5% and 52.5%, respectively. Regarding T4 disease, 3-year overall and laryngectomy-free survival were 58.3% and 38.5%, respectively.ConclusionsThis study, the first prospective study for cervical esophageal cancer, showed that chemoradiotherapy has sufficient efficacy and safety for use as an alternative to surgery for these patients.
Teaser
This multi-center phase II study is the first prospective study that showed chemoradiotherapy (5-FU/CDDP/RT) for cervical esophageal cancer has sufficient efficacy and safety for use as an alternative to surgery.from Cancer via ola Kala on Inoreader http://ift.tt/2bKSYOn
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Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma
Source:European Journal of Cancer, Volume 67
Author(s): Dirk Schadendorf, Reinhard Dummer, Axel Hauschild, Caroline Robert, Omid Hamid, Adil Daud, Alfons van den Eertwegh, Lee Cranmer, Steven O'Day, Igor Puzanov, Jacob Schachter, Christian Blank, April Salama, Carmen Loquai, Janice M. Mehnert, Darcy Hille, Scot Ebbinghaus, S. Peter Kang, Wei Zhou, Antoni Ribas
BackgroundIn KEYNOTE-002, pembrolizumab significantly prolonged progression-free survival and was associated with a better safety profile compared with chemotherapy in patients with advanced melanoma that progressed after ipilimumab. We present health-related quality of life (HRQoL) outcomes from KEYNOTE-002.MethodsPatients were randomly assigned 1:1:1 to pembrolizumab 2 or 10 mg/kg every 3 weeks (Q3W) or investigator-choice chemotherapy. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 instrument. A constrained longitudinal data analysis model was implemented to assess between-arm differences in HRQoL scores. The study is registered with ClinicalTrials.gov, number NCT01704287.ResultsOf the 540 patients enrolled, 520 were included in the HRQoL analysis. Baseline global health status (GHS) was similar across treatment arms. Compliance rates at week 12 were 76.6% (n = 108), 82.3% (n = 121), and 86.4% (n = 133) for the control, pembrolizumab 2 mg/kg Q3W, and pembrolizumab 10 mg/kg Q3W arms, respectively. From baseline to week 12, GHS/HRQoL scores were maintained to a higher degree in the pembrolizumab arms compared with the chemotherapy arm (decrease of −2.6 for each pembrolizumab arm versus −9.1 for chemotherapy; P = 0.01 for each pembrolizumab arm versus chemotherapy). Fewer patients treated with pembrolizumab experienced deterioration in GHS at week 12 (31.8% for pembrolizumab 2 mg/kg, 26.6% for 10 mg/kg, and 38.3% for chemotherapy), with similar trends observed for the individual functioning and symptoms scales.ConclusionsHRQoL was better maintained with pembrolizumab than with chemotherapy in KEYNOTE-002, supporting the use of pembrolizumab in patients with ipilimumab-refractory melanoma.
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A case-matched study of stereotactic radiosurgery for patients with brain metastases: comparing treatment results for those with versus without neurological symptoms
Abstract
We aimed to reappraise whether post-stereotactic radiosurgery (SRS) results for brain metastases differ between patients with and without neurological symptoms. This was an institutional review board-approved, retrospective cohort study using our prospectively accumulated database including 2825 consecutive BM patients undergoing gamma knife SRS alone during the 15-year period since July 1998. The 2825 patients were divided into two groups; neurologically asymptomatic [group A, 1374 patients (48.6 %)] and neurologically symptomatic [group B, 1451 (51.4 %)]. Because there was considerable bias in pre-SRS clinical factors between groups A and B, a case-matched study was conducted. Ultimately, 1644 patients (822 in each group) were selected. The standard Kaplan–Meier method was used to determine post-SRS survival. Competing risk analysis was applied to estimate cumulative incidences of neurological death, neurological deterioration, local recurrence, re-SRS for new lesions and SRS-induced complications. Post-SRS median survival times (MSTs) did not differ between the two groups; 7.8 months in group A versus 7.4 months in group B patients (HR 1.064, 95 % CI 0.963–1.177, p = 0.22). However, cumulative incidences of neurological death (HR 1.637, 95 % CI 1.174–2.281, p = 0.0036) and neurological deterioration (HR 1.425, 95 % CI 1.073–1.894, p = 0.014) were significantly lower in the group A than in the group B patients. Neurologically asymptomatic patients undergoing SRS for BM had better results than symptomatic patients in terms of both maintenance of good neurological state and prolonged neurological survival. Thus, we conclude that screening computed tomography/magnetic resonance imaging is highly beneficial for managing cancer patients.
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Venous thromboembolism prophylaxis in brain tumor patients undergoing craniotomy: a meta-analysis
Abstract
Brain tumor patients undergoing craniotomy generally receive prophylaxis against venous thromboembolism (VTE), but modalities in use differ widely and have been debated in the literature. A systematic review and meta-analysis was conducted to assess the efficacy and safety of VTE prophylaxis among brain tumor patients undergoing craniotomy. Ten randomized controlled trials were included in the final efficacy analysis. The various prophylactic measures employed in these studies reduced the risk for thrombosis compared to controls with an overall risk ratio of 0.61 (95 % CI: 0.47–0.79) in the fixed effect model. Although Cochrane Q-test showed unimportant heterogeneity across studies (p = 0.19) and the I2, a measure of heterogeneity between studies, was reasonably low at 28 %, subgroup analysis indicated that intervention type was a potential effect modifier for efficacy (p = 0.04). Unfractionated heparin alone showed a stronger reduction in VTE risk compared to placebo (RR = 0.27; 95 % CI: 0.10–0.73), and LMWH combined with mechanical prophylaxis showed a lower VTE risk as compared to mechanical prophylaxis alone (0.61; 95 % CI: 0.46–0.82). This meta-analysis demonstrates a statistically significant VTE risk reduction among brain tumor patients receiving prophylaxis, with chemical prophylaxis showing the strongest risk reduction. Five studies were included in the safety analysis, which showed an overall increased risk of bleeding comparing different prophylactic measures to different controls (RR = 2.02; 95 % CI: 1.14–3.58; I2 = 0 %; p = 0.86). Interventions in these studies were associated with an increased risk of post-operative, minor hemorrhage (RR = 2.20; 95 % CI = 1.00; 4.85), while the risk of major hemorrhage was not increased by chemoprophylaxis.
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Utah Cancer Survivors: A Comprehensive Comparison of Health-Related Outcomes Between Survivors and Individuals Without a History of Cancer
Abstract
Assessments of cancer survivors' health-related needs are often limited to national estimates. State-specific information is vital to inform state comprehensive cancer control efforts developed to support patients and providers. We investigated demographics, health status/quality of life, health behaviors, and health care characteristics of long-term Utah cancer survivors compared to Utahans without a history of cancer. Utah Behavioral Risk Factor Surveillance System (BRFSS) 2009 and 2010 data were used. Individuals diagnosed with cancer within the past 5 years were excluded. Multivariable survey weighted logistic regressions and computed predictive marginals were used to estimate age-adjusted percentages and 95 % confidence intervals (CI). A total of 11,320 eligible individuals (727 cancer survivors, 10,593 controls) were included. Respondents were primarily non-Hispanic White (95.3 % of survivors, 84.1 % of controls). Survivors were older (85 % of survivors ≥40 years of age vs. 47 % of controls). Survivors reported the majority of their cancer survivorship care was managed by primary care physicians or non-cancer specialists (93.5 %, 95 % CI = 87.9–99.1). Furthermore, 71.1 % (95 % CI = 59.2–82.9) of survivors reported that they did not receive a cancer treatment summary. In multivariable estimates, fair/poor general health was more common among survivors compared to controls (17.8 %, 95 % CI = 12.5–23.1 vs. 14.2 %, 95 % CI = 12.4–16.0). Few survivors in Utah receive follow-up care from a cancer specialist. Provider educational efforts are needed to promote knowledge of cancer survivor issues. Efforts should be made to improve continuity in follow-up care that addresses the known issues of long-term survivors that preclude optimal quality of life, resulting in a patient-centered approach to survivorship.
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Epothilone B induces apoptosis and enhances apoptotic effects of ABT-737 on human cancer cells via PI3K/AKT/mTOR pathway
Abstract
Purpose
Epothilone B and its derivatives are tested in multiple clinical trials. Epothilone B induces neurotoxic effect in clinical trials; however, low-dose epothilone B regimen can promote neuroprotection and neurogenesis. Thus, the study of new combination chemotherapy regimen incorporating low-dose epothilone B with other chemotherapeutic agents might help to develop epothilone B-based approaches to cancer treatment and avoid the neurotoxicity of epothilone B.
Methods
Cell proliferation was assessed by SRB cell viability assay. Apoptosis was analyzed by propidium iodide (PI) staining. Mitochondrial membrane depolarization was evaluated using JC-1 staining. The expression of proteins was detected by western blotting.
Results
In this study, we demonstrated that the combination of ABT-737 and low-dose epothilone B showed synergistic anti-proliferation effects on human cancer cells. In addition, epothilone B + ABT-737 synergy was through mitochondria-mediated apoptosis pathway. Furthermore, combination treatment markedly induced the activation of caspase-3 and the cleavage of PARP. The activation of PI3K/Akt/mTOR pathway is associated with resistance to epothilone B. Our data showed that epothilone B plus ABT-737 resulted in a blockade of the PI3K/AKT/mTOR signaling pathway.
Conclusions
These data indicate that ABT-737 may be a pertinent sensitizer to epothilone B, and the strategy of combining epothilone B with ABT-737 appears to be an attractive option for overcoming the resistance and neurotoxicity of epothilone B.
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Ganoderic acid targeting multiple receptors in cancer: in silico and in vitro study
Abstract
Receptor tyrosine kinases (RTKs) are transmembrane high-affinity surface receptors responsible for cell migration, adhesion, apoptosis, metabolism, and cell proliferation activities in various cancers. Minute aberration in the RTK signaling modulates the downstream signaling pathways that results in cancer. Ganoderic acid is a triterpene isolated from Ganoderma lucidum, which is renowned for its therapeutics effect, especially in cancer. The present study discusses receptor-based molecular docking of insulin receptor (IR), insulin-like growth factor receptor 1 (IGFR-1), vascular endothelial growth factor receptor-1 (VEGFR-1), vascular endothelial growth factor receptor-2 (VEGFR-2), and estrogen receptor (ER) with 50 isoforms of ganoderic acid along with natural inhibitors. These receptors were assessed for toxicity (ADMET) by using Maestro 9.6 (Schrödinger Inc). The calculated docking free energy yielded an excellent dock score for the ganoderic acid when docked with proteins IR, IGFR-1, VEGFR-1, VEGFR-2, and ER, suggesting its potential in combating cancer. Protein–ligand profile highlighted the binding interactions comprising lipophilic, hydrogen bonding, pi-pi stacking interactions, and noncovalent bonding which play a pivotal role in targeting cancer. In silico studies revealed structure of ganoderic acid A as best isoforms among 50 isoforms which exhibits biological activity in liver cancer cells. Ganoderic acids A significantly decrease the viability, proliferation, and oxidative stress in a dose-dependent manner in liver cancer cells.
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Temporal changes in the cervical cancer burden in Bulgaria: Implications for eastern european countries going through transition
Publication date: October 2016
Source:Cancer Epidemiology, Volume 44
Author(s): Kaeli K. Samson, Gleb Haynatzki, Amr S. Soliman, Zdravka Valerianova
IntroductionIn most developed countries, incidence of cervical cancer declined likely due to well-established cervical cancer screening programs. However, such decline has not been identified in Eastern Europe, where such programs are not well established.MethodsThis study utilized data of the Bulgarian Cancer Registry for the period 1993–2013. Age-standardized incidence and mortality trends were analyzed using Joinpoint regression. Maps were created to illustrate spatial distributions of rates.ResultsThe northern region of Bulgaria showed a larger cervical cancer burden than the southern region and rural women tended to be diagnosed at older ages (p<0.0001) and later stages (p<0.0001) than urban women. The distribution of disease stages changed over the 21 years, with most common stages of diagnosis being stage II in 1993 (39.2%) to stage I in 2013 (44.7%; p<0.0001). While age-standardized mortality slightly increased over the 21 years (from 4.8 to 5.2 per 100,000; p=0.009), age-standardized incidence increased from 14.0 to 21.4 per 100,000 up until 2006 (p<0.001), after which it plateaued.ConclusionsThe lack of a similar plateau in mortality may be because the second most prevalent stage of diagnosis in recent years was stage III, indicating diagnosis at advanced symptomatic stages. Cervical cancer incidence is expected to continue to decrease if screening programs are strengthened and human papillomavirus vaccines are widely utilized. As Bulgaria has shared cervical cancer trends with other Eastern European countries in the past, it may be beneficial to develop future prevention interventions based on a regional, rather than a country-specific level.
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A case of metastatic renal cell carcinoma showing complete remission after cytoreductive nephrectomy followed by temsirolimus
Abstract
Here, we present a case report of a patient with poor-risk advanced renal cell carcinoma who had a complete remission after cytoreductive nephrectomy followed by temsirolimus. A 67-year-old woman was diagnosed with advanced renal cell carcinoma, stage pT3aN2M1 in April 2013. In the Memorial Sloan-Kettering Cancer Center criteria, she had three prognostic factors and was classified into the poor-risk category. After 23 weeks of treatment with temsirolimus, complete remission was achieved. Temsirolimus treatment was discontinued after 23 weeks because of grade 3 toxicity noninfectious pneumonitis. Five months after beginning steroid treatment without temsirolimus, a CT scan showed no new metastatic lesion or progression of disease. This was a very rare case with achievement of a complete remission after cytoreductive nephrectomy followed by temsirolimus.
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Irinotecan- and 5-fluorouracil-induced intestinal mucositis: insights into pathogenesis and therapeutic perspectives
Abstract
Purpose
Intestinal mucositis and diarrhea are common manifestations of anticancer regimens that include irinotecan, 5-fluorouracil (5-FU), and other cytotoxic drugs. These side effects negatively impact therapeutic outcomes and delay subsequent cycles of chemotherapy, resulting in dose reductions and treatment discontinuation. Here, we aimed to review the experimental evidence regarding possible new targets for the management of irinotecan- and 5-FU-related intestinal mucositis.
Methods
A literature search was performed using the PubMed and MEDLINE databases. No publication time limit was set for article inclusion.
Results
Here, we found that clinical management of intestinal mucositis and diarrhea is somewhat ineffective at reducing symptoms, possibly due to a lack of specific targets for modulation. We observed that IL-1β contributes to the apoptosis of enterocytes in mucositis induced by 5-FU. However, 5-FU-related mucositis is far less thoroughly investigated with regard to specific molecular targets when compared to irinotecan-related disease. Several studies have proposed that a correlation exists between the intestinal microbiota, the enterohepatic recirculation of active metabolites of irinotecan, and the establishment of mucositis. However, as reviewed here, this association seems to be controversial. In addition, the pathogenesis of irinotecan-induced mucositis appears to be orchestrated by interleukin-1/Toll-like receptor family members, leading to epithelial cell apoptosis.
Conclusions
IL-1β, IL-18, and IL-33 and the receptors IL-1R, IL-18R, ST2, and TLR-2 are potential therapeutic targets that can be modulated to minimize anticancer agent-associated toxicity, optimize cancer treatment dosing, and improve clinical outcomes. In this context, the pathogenesis of mucositis caused by other anticancer agents should be further investigated.
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Potential influence of being overweight on the development of hepatic dysfunction in Japanese patients with EGFR-mutated non-small cell lung cancer undergoing gefitinib monotherapy: the Okayama Lung Cancer Study Group experience
Abstract
Background
Being overweight has been reported to induce hepatic dysfunction during cytotoxic chemotherapy. Severe hepatic dysfunction can also be observed during gefitinib monotherapy, leading to interrupted or discontinued treatment. However, whether being overweight is a risk factor during gefitinib therapy is unknown.
Methods
We retrospectively reviewed 183 Japanese patients with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor-naïve non-small cell lung cancer (NSCLC) harboring EGFR mutations, who received gefitinib monotherapy between July 2007 and February 2014. We defined being overweight as having a body mass index (BMI) ≥ 25 kg/m2 and assessed its potential relationship with ≥grade 2 hepatic dysfunction.
Results
The patient demographics were as follows: 114 women; median age 72 years (range 42–95 years); BMI ≥ 25 kg/m2, n = 32; performance status 0–1, n = 136; stage IIIB/IV, n = 141; and major EGFR mutations, n = 171. Hepatic dysfunction ≥grade 2 during the gefitinib therapy was observed in 44 (24.0 %) patients, 22 (50.0 %) of whom interrupted or discontinued treatment. The median duration from gefitinib administration to the development of hepatic dysfunction was 56 days (range 6–1,352 days). Overweight patients were more likely to develop hepatic dysfunction ≥grade 2 compared to non-overweight patients according to a multivariate analysis adjusted for several confounding factors (hazard ratio 2.24; 95 % confidence interval 1.01–4.95; p = 0.046).
Conclusion
These results suggest that being overweight may induce hepatic dysfunction during gefitinib monotherapy in Japanese patients with EGFR-mutated NSCLC.
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Grid-Independent Descriptors (GRIND) analysis and SAR Guided Molecular Docking Studies to Probe Selectivity Profiles of Inhibitors of Multidrug Resistance Transporters ABCB1 and ABCG2.
Grid-Independent Descriptors (GRIND) analysis and SAR Guided Molecular Docking Studies to Probe Selectivity Profiles of Inhibitors of Multidrug Resistance Transporters ABCB1 and ABCG2.
Curr Cancer Drug Targets. 2016 Aug 31;
Authors: Shafi T, Jabeen I
Abstract
ATP-binding cassette (ABC) transporters, P-glycoprotein (P-gp, ABCB1) and breast cancer resistance protein (BCRP/ABCG2) are major determinant of pharmacokinetic, safety and efficacy profiles of drugs thereby effluxing a broad range of endogenous substances across the plasma membrane. Overexpression of these transporters in various tumors is also implicated in the development of multidrug resistance (MDR) and thus, hampers the success of cancer chemotherapy. Modulators of these efflux transporters in combination with chemotherapeutics could be a promising concept to increase the effective intracellular concentration of anticancer drugs. However, broad and overlapped specificity for substrates and modulators of ABCB1 and ABCG2, merely induce toxicity and unwanted drug-drug interactions and thus, lead to late-stage failure of drugs. Therefore, it is of great importance to identify specific 3D structural requirements for selective inhibition of ABCB1 and ABCG2 transport function. Towards this goal, GRID Independent Molecular Descriptor (GRIND) models of selective inhibitors of both transporters have been developed, using their most probable binding conformations obtained from molecular docking protocol. Our results demonstrated a dominant role of molecular shape and different H-bonding patterns in drug-ABCB1/ABCG2 selective interactions. Moreover, distinct distances of different pharmacophoric features from steric hot spots of the molecules provided a strong basis of selectivity for both transporters. Additionally, our results suggested the presence of two H-bond donors at a distance of 8.4-8.8 A° in selective modulators of ABCG2.
PMID: 27585695 [PubMed - as supplied by publisher]
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Radiothérapie conformationnelle avec modulation d’intensité des cancers des voies aérodigestives supérieures : dose de tolérance des tissus sains. Muscles constricteurs du pharynx et larynx
Source:Cancer/Radiothérapie
Author(s): P. Graff, V. Woisard, S. Racadot, J. Thariat, Y. Pointreau
Les troubles fonctionnels chroniques affectant le pharyngolarynx ont émergé parmi les effets secondaires radio-induits impactant la qualité de vie des patients atteints de cancer de la sphère ORL survivant à long terme. Plusieurs structures anatomiques impliquées dans le fonctionnement complexe de cette région ont été identifiées. Une limitation de la dose délivrée sur ces structures pourrait contribuer à réduire les risques d'œdème laryngé, de dysphonie et surtout de dysphagie. Quelques recommandations dosimétriques peuvent être émises, comme maintenir la dose moyenne aux constricteurs du pharynx en dessous de 50 à 55Gy, la dose moyenne délivrée au larynx sus-glottique en dessous de 40 à 45Gy et si possible la dose moyenne délivrée au larynx glottique en dessous de 20Gy. Une épargne des muscles du plancher de la bouche et de l'œsophage cervical serait également bénéfique. Néanmoins, la qualité des données bibliographiques ne permet pas de considérer de telles recommandations comme suffisantes. Il est préconisé de retenir une philosophie d'épargne maximale des structures suscitées, la qualité de couverture des volumes cibles tumoraux restant prioritaire.Radio-induced pharyngolaryngeal chronic disorders may challenge the quality of life of head and neck cancer long survivors. Many anatomic structures have been identified as potentially impaired by irradiation and responsible for laryngeal edema, dysphonia and dysphagia. Some dose constraints might be plausible such as keeping the mean dose to the pharyngeal constrictor muscles under 50 to 55Gy, the mean dose to the supra-glottic larynx under 40 to 45Gy and, if feasible, the mean dose to the glottic larynx under 20Gy. A reduction of the dose delivered to the muscles of the floor of the mouth and the cervical esophagus would be beneficial as well. Nevertheless, the publications available do not provide an extensive enough level of proof. One should consider limiting as low as possible the dose delivered to these structures without compromising the quality of irradiation of the target tumor volumes.
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Argumentaire clinique pour la radiothérapie guidée par imagerie par résonance magnétique
Source:Cancer/Radiothérapie
Author(s): P. Maingon
Le concept de radiothérapie guidée par l'image bénéficie du développement de l'imagerie par résonance magnétique (IRM), associée à ces différentes capacités d'analyse des tissus, comme la spectroscopie ou les études de diffusion. La mise à disposition d'un dispositif de repositionnement des patients faisant appel à l'imagerie par résonance magnétique représente une valeur ajoutée incontestable, ne délivrant aucune dose additionnelle au patient durant son traitement tout en optimisant les stratégies adaptatives grâce à son contraste supérieur à la scanographie pour les tissus mous. Ses avantages sont connus pour les tumeurs cérébrales, les cancers des voies aérodigestives supérieures, les tumeurs pelviennes et thoraciques, les cancers digestifs. La radiothérapie adaptative est un concept qui inaugure une étape nouvelle du développement de la radiothérapie moderne selon différentes modalités. Plusieurs solutions technologiques sont étudiées et proposées aux cliniciens afin de faire bénéficier les patients de ces avancées technologiques.The concept of image-guided radiotherapy benefits from the development of magnetic resonance imaging (MRI) associated with different capacities of tissue analyses such as spectroscopy or diffusion analysis. The production of devices allowing the repositioning of patients through MRI represents a strong added value without delivering any additional dose to the patient while the optimization of the adaptative strategies are facilitated by a better contrast of the soft tissues compared to the scanner. The advantages of MRI are well demonstrated for brain tumours, head and neck carcinomas, pelvic tumors, mediastinal malignancies, gastrointestinal tract diseases. Adaptative radiotherapy inaugurates a new area of radiotherapy with different modalities. Several technological solutions are provided or discussed allowing the patients to benefit from thses new technologies as soon as possible.
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