Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Σάββατο 14 Μαΐου 2016
The association between attention-deficit/hyperactivity (ADHD) symptoms and self-employment
Abstract
Attention-deficit/hyperactivity (ADHD) symptoms have been associated with the decision to become self-employed. Although these symptoms are generally regarded as disadvantageous, there may also be a bright side. To our knowledge, however, there has been no systematic, epidemiological evidence to support this claim. This paper examines the association between ADHD symptoms and self-employment in a population-based sample from the STAGE cohort of the Swedish Twin Registry (N = 7208). For replication, we used a sample of Dutch students who participated in the Global University Entrepreneurial Spirit Students' Survey (N = 13,112). In the Swedish sample, we found a positive association with self-employment for both general ADHD symptoms [odds ratio (OR) 1.13; 95 % confidence intervals (CI) 1.04–1.23] and hyperactivity symptoms [OR 1.19; 95 % CI 1.08–1.32], whereas no association was found for attention-deficit symptoms [OR 0.99; 95 % CI 0.89–1.10]. The positive association between hyperactivity and self-employment was replicated in the Dutch student sample [OR 1.09; 95 % CI 1.03–1.15]. Our results show that certain aspects of ADHD, in particular hyperactivity, can have a bright side, as they are positively associated with self-employment.
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Disability and all-cause mortality in the older population: evidence from the English Longitudinal Study of Ageing
Abstract
Despite the vast body of literature studying disability and mortality, evidence to support their association is scarce. This work investigates the role of disability in explaining all‐cause mortality among individuals aged 50+ who participated in the English Longitudinal Study of Aging. The aim is to explain the gender paradox in health and mortality by analysing whether the association of disability with mortality differs between women and men. Disability was conceived following the International Classification of Functioning, Disability and Health (ICF), proposed by the WHO, that conceptualizes disability as a combination of three components: impairment, activity limitation and participation restriction. Latent variable models were used to identify domain-specific factors and general disability. The association of the latter with mortality up to 10 years after enrolment was estimated using discrete-time survival analysis. Our work confirms the validity of the ICF framework and finds that disability is strongly associated with mortality, with a time-varying effect among men, and a smaller constant effect for women. Adjusting for demographic, socioeconomic and behavioural factors attenuated the association for both sexes, but overall the effects remained high and significant. These findings confirm the existence of gender paradox by showing that, when affected by disability, women survive longer than men, although if men survive the first years they appear to become more resilient to disability. Sensitivity analyses suggested that the gender paradox cannot be solely explained by gender-specific health conditions: there must be other mechanisms acting within the pathway between disability and mortality that need to be explored.
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Suicide in married couples in Sweden: Is the risk greater in same-sex couples?
Abstract
Minority sexual orientation is a predictor of suicide ideation and attempts, though its association with suicide mortality is less clear. We capitalize on Sweden's extensively linked databases, to investigate whether, among married individuals, same-sex marriage is associated with suicide. Using a population-based register design, we analyzed suicide risk among same-sex married women and men (n = 6456), as compared to different-sex married women and men (n = 1181723) in Sweden. We selected all newly partnered or married individuals in the intervening time between 1/1/1996 and 12/31/2009 and followed them with regard to suicide until 12/31/2011. Multivariate Poisson regression was used to calculate adjusted incidence risk ratios (IRR) with 95 % confidence intervals (CI). The risk of suicide was higher among same-sex married individuals as compared to different-sex married individuals (IRR 2.7, 95 % CI 1.5–4.8), after adjustment for time at risk and socioeconomic confounding. Sex-stratified analyses showed a tentatively elevated risk for same-sex married women (IRR 2.5, 95 % CI 0.8–7.7) as compared to different-sex married women. Among same-sex married men the suicide risk was nearly three-fold greater as compared to different-sex married (IRR 2.895 % CI 1.5–5.5). This holds true also after adjustment for HIV status. Even in a country with a comparatively tolerant climate regarding homosexuality such as Sweden, same-sex married individuals evidence a higher risk for suicide than other married individuals.
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How much do tumor stage and treatment explain socioeconomic inequalities in breast cancer survival? Applying causal mediation analysis to population-based data
Abstract
Substantial socioeconomic inequalities in breast cancer survival persist in England, possibly due to more advanced cancer at diagnosis and differential access to treatment. We aim to disentangle the contributions of differential stage at diagnosis and differential treatment to the socioeconomic inequalities in cancer survival. Information on 36,793 women diagnosed with breast cancer during 2000–2007 was routinely collected by an English population-based cancer registry. Deprivation was determined for each patient according to her area of residence at the time of diagnosis. A parametric implementation of the mediation formula using Monte Carlo simulation was used to estimate the proportion of the effect of deprivation on survival mediated by stage and by treatment. One-third (35 % [23–48 %]) of the higher mortality experienced by most deprived patients at 6 months after diagnosis, and one tenth (14 % [−3 to 31 %]) at 5 years, was mediated by adverse stage distribution. We initially found no evidence of mediation via differential surgical treatment. However, sensitivity analyses testing some of our study limitations showed in particular that up to thirty per cent of the higher mortality in most deprived patients could be mediated by differential surgical treatment. This study illustrates the importance of using causal inference methods with routine medical data and the need for testing key assumptions through sensitivity analyses. Our results suggest that, although effort for earlier diagnosis is important, this would reduce the cancer survival inequalities only by a third. Because of data limitations, role of differential surgical treatment may have been under-estimated.
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Phase I safety and pharmacokinetic dose-escalation study of pilaralisib polymorph E, a phosphoinositide 3-kinase inhibitor in tablet formulation, in patients with solid tumors or lymphoma
Abstract
Purpose
Pilaralisib (SAR245408), a pan-class I PI3K inhibitor, has been investigated in Phase I/II trials in several solid tumors and lymphomas in capsule and tablet formulations of polymorph A (capsule-A and tablet-A). This Phase I study was conducted to determine the recommended Phase II dose (RP2D) of a more thermodynamically stable form of pilaralisib (polymorph E), in tablet formulation (tablet-E), in patients with advanced solid tumors or relapsed/refractory lymphoma.
Methods
A modified '3 + 3' dose-escalation design was employed. Patients received pilaralisib once daily (QD; starting dose 400 mg) for two 28-day cycles. Primary endpoints were safety and pharmacokinetics (PK). Exploratory endpoints were pharmacodynamics and efficacy.
Results
Eighteen patients were enrolled: Six patients received pilaralisib 400 mg QD and 12 patients received pilaralisib 600 mg QD. Two patients in the 600 mg QD cohort had dose-limiting toxicities (DLTs) (one patient with Grade 3 maculopapular rash and one patient with Grade 3 generalized rash and Grade 4 lipase increased). The most frequently occurring treatment-related, treatment-emergent adverse events were decreased appetite (22 %), dry skin (22 %), nausea (22 %) and vomiting (22 %). In PK analyses, individual exposures observed with 600 mg tablet-E were within the range of data at steady state from previous studies of 400 mg tablet-A and 600 mg capsule-A. Five patients (28 %) had stable disease as best response.
Conclusions
With pilaralisib tablet-E, the RP2D was 600 mg QD, drug exposure was similar to the 400 mg tablet-A and 600 mg capsule-A formulations, and safety was consistent with the known safety profile of pilaralisib.
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Everolimus pharmacokinetics and its exposure–toxicity relationship in patients with thyroid cancer
Abstract
Background
Everolimus is a mTOR inhibitor used for the treatment of different solid malignancies. Many patients treated with the registered fixed 10 mg dose once daily are in need of dose interruptions, reductions or treatment discontinuation due to severe adverse events. This study determined the correlation between systemic everolimus exposure and toxicity. Additionally, the effect of different covariates on everolimus pharmacokinetics (PK) was explored.
Methods
Forty-two patients with advanced thyroid carcinoma were treated with 10 mg everolimus once daily. Serial pharmacokinetic sampling was performed on days 1 and 15. Subsequently, a population PK model was developed using NONMEM to estimate individual PK values used for analysis of an exposure–toxicity relationship. Furthermore, this model was used to investigate the influence of patient characteristics and genetic polymorphisms in genes coding for enzymes relevant in everolimus PK.
Results
Patients who required a dose reduction (n = 18) due to toxicity at any time during treatment had significant higher everolimus exposures [mean AUC0–24 (SD) 600 (274) vs. 395 (129) µg h/L, P = 0.008] than patients without a dose reduction (n = 22). A significant association between everolimus exposure and stomatitis was found in the four-level ordered logistic regression analysis (P = 0.047). The presence of at least one TTT haplotype in the ABCB1 gene was associated with a 21 % decrease in everolimus exposure.
Conclusion
The current study showed that dose reductions and everolimus-induced stomatitis were strongly associated with systemic everolimus drug exposure in patients with cancer. Our findings confirm observations from another study in patients with cancer and show us that everolimus is a good candidate for individualized dosing in patients with cancer.
ClinicalTrial.gov number
NCT01118065.
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Clinical and pharmacologic evaluation of two dosing schedules of indotecan (LMP400), a novel indenoisoquinoline, in patients with advanced solid tumors
Abstract
Purpose
Indenoisoquinolines are non-camptothecin topoisomerase I (TopI) inhibitors that overcome the limitations of camptothecins: chemical instability and camptothecin resistance. Two dosing schedules of the novel indenoisoquinoline, indotecan (LMP400), were evaluated in patients with advanced solid tumors.
Methods
The maximum tolerated dose (MTD), toxicities, and pharmacokinetics of two indotecan drug administration schedules (daily for 5 days or weekly) were investigated. Modulation of TopI and the phosphorylation of histone H2AX (γH2AX) were assayed in tumor biopsies; γH2AX levels were also evaluated in circulating tumor cells (CTCs) and hair follicles to assess DNA damage response.
Results
An MTD of 60 mg/m2/day was established for the daily regimen, compared to 90 mg/m2 for the weekly regimen. The TopI response to drug showed target engagement in a subset of tumor biopsies. Pharmacokinetics profiles demonstrated a prolonged terminal half-life and tissue accumulation compared to topotecan. Dose-dependent decreases in total CTCs were measured in seven patients. Formation of γH2AX-positive foci in CTCs (day 3) and hair follicles (4–6 h) was observed following treatment.
Conclusions
We established the MTD of two dosing schedules for a novel TopI inhibitor, indotecan. Target engagement was demonstrated as Top1 downregulation and γH2AX response. No objective responses were observed on either schedule in this small patient cohort. The principal toxicity of both schedules was myelosuppression; no significant gastrointestinal problems were observed. Increased DNA damage response was observed in CTCs, hair follicles, and a subset of tumor biopsies.
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Mitochondria: Inadvertent targets in chemotherapy-induced skeletal muscle toxicity and wasting?
Abstract
Chemotherapy has been associated with increased mitochondrial reactive oxygen species production, mitochondrial dysfunction and skeletal muscle atrophy leading to severe patient clinical complications including skeletal muscle fatigue, insulin resistance and wasting. The exact mechanisms behind this skeletal muscle toxicity are largely unknown, and as such co-therapies to attenuate chemotherapy-induced side effects are lacking. Here, we review the current literature describing the clinical manifestations and molecular origins of chemotherapy-induced myopathy with a focus on the mitochondria as the target organelle via which chemotherapeutic agents establish toxicity. We explore the likely mechanisms through which myopathy is induced, using the anthracycline doxorubicin, and the platinum-based alkylating agent oxaliplatin, as examples. Finally, we recommend directions for future research and outline the potential significance of these proposed directions.
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A comprehensive pharmacokinetic/pharmacodynamics analysis of the novel IGF1R/INSR inhibitor BI 893923 applying in vitro, in vivo and in silico modeling techniques
Abstract
Purpose
BI 893923 is a novel IGF1R/INSR tyrosine kinase inhibitor demonstrating anti-tumor efficacy and good tolerability. We aimed to characterize the relationship between BI 893923 plasma concentration, tumor biomarker modulation, tumor growth and hyperglycemia in mice using in silico modeling analyses.
Methods
In vitro molecular and cellular assays were used to demonstrate the potency and selectivity of BI 893923. Diverse in vitro DMPK assays were used to characterize the compound's drug-like properties. Mice xenografted with human GEO tumors were treated with different doses of BI 893923 to demonstrate the compound's efficacy, biomarker modulation and tolerability. PK/PD analyses were performed using nonlinear mixed-effects modeling.
Results
BI 893923 demonstrated potent and selective molecular inhibition of the IGF1R and INSR and demonstrated attractive drug-like properties (permeability, bioavailability). BI 893923 dose-dependently reduced GEO tumor growth and demonstrated good tolerability, characterized by transient hyperglycemia and normal body weight gain. A population PK/PD model was developed, which established relationships between BI 893923 pharmacokinetics, hyperglycemia, pIGF1R reduction and tumor growth.
Conclusion
BI 893923 demonstrates molecular properties consistent with a highly attractive inhibitor of the IGF1R/INSR. A generic PK/PD model was developed to support preclinical drug development and dose finding in mice.
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Gibberellin derivative GA-13315 sensitizes multidrug-resistant cancer cells by antagonizing ABCB1 while agonizes ABCC1
Abstract
Purpose
GA-13315 is a gibberellin derivative that reveals antitumor and antineoplastic effects both in vitro and in vivo. In the present study, the chemosensitizing effects of GA-13315 in multidrug-resistant cell lines were examined and the underlying mechanisms were investigated.
Methods
Cytotoxicity and chemosensitizing effects of GA-13315 were determined by MTT assay. Function of ABC transporter was analyzed by measuring intracellular drug accumulation of doxorubicin and rhodamine 123 and by determining the ATPase activity of ABC transporter. Expression levels of apoptosis regulators were analyzed using real-time quantitative PCR and Western blot.
Results
GA-13315 selectively killed MCF-7/adr cells that overexpress P-glycoprotein (ABCB1) over the parent MCF-7 cells. In combination with conventional chemotherapeutic agents, GA-13315 at sub-toxic concentrations reversed the multidrug resistance mediated by ABCB1 but exacerbated the resistance conferred by multidrug resistance-associated protein 1 (ABCC1). GA-13315 increased intracellular accumulation of doxorubicin and rhodamine 123 in MCF-7/adr cells and in ABCB1-transfected HEK293 cells but facilitated drug flush-out from cells that overexpress ABCC1. GA-13315 inhibited the ATPase activity of ABCB1 while stimulated that of ABCC1. Moreover, the downregulated expression of Bax in MCF-7/adr cells was restored by GA-13315 markedly.
Conclusion
These data suggest that GA-13315 sensitizes multidrug-resistant cells at least partially by impeding the efflux function of ABCB1. The upregulation of Bax by GA-13315 may also contribute to the sensitizing action. The opposite effects of GA-13315 on different ATP-binding cassette transporters and their implications in overcoming drug resistance require further investigation.
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New Treatment Target Identified for Diffuse Large B-Cell Lymphoma
NCI researchers have identified new therapeutic targets in a common subtype of diffuse large B-cell lymphoma (DLBCL). Drugs that hit these targets, known as SMAC mimetics, are already under clinical development, and the research team hopes to begin testing them in clinical trials of patients with DLBCL.
In a study published April 11 in Cancer Cell, the NCI researchers showed that the proteins cIAP1 and cIAP2 control the activity of a key signaling pathway in B cells that drives proliferation and survival in the ABC subtype of DLBCL (ABC DLBCL). In cell lines and animal models of the ABC subtype, they found that SMAC mimetics, which inhibit cIAP1 and cIAP2, killed cancer cells and shrank tumors.
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DDR1 enhances invasion and metastasis of gastric cancer via epithelial-mesenchymal transition
Abstract
In this study, we investigated the effects of DDR1 on the invasion and metastasis in gastric cancer (GC) via epithelial-mesenchymal transition (EMT). Immunohistochemistry analysis was used to detect DDR1, E-cadherin, and Vimentin expression in GC tissues as well as DDR1 expression in GC cell lines and normal gastric epithelial cells. The relationship between DDR1 expression and EMT in GC cell lines was explored by down and upregulating DDR1 and examining corresponding changes in the expression of EMT-related proteins and in biological characteristics. Furthermore, a nude mice model with a transplantation tumor generating from stably transfected GC cells with DDR1 overexpression was established and performed to further reveal the effects of DDR1 expression on cellular morphology and growth of GC. Our results showed that DDR1 was highly expressed in GC tissues and cell lines compared with adjacent tissues and normal cell line, and its expression was significantly higher in GC having poor differentiation (p < 0.01), advanced depth of wall invasion (p = 0.020), lymph node metastasis (p = 0.0001), liver metastasis (p < 0.01), and high TNM stage (p < 0.01). Western blot analyses revealed that DDR1 overexpression resulted in a significant decrease in the expression of E-cadherin (p < 0.01) and an increase in the expression of Vimentin and Snail (p < 0.01), while knockdown of DDR1 led to opposite outcomes. We further demonstrated that DDR1 overexpression promoted GC cell proliferation (p < 0.05), migration (p < 0.01), and invasion (p < 0.01), and accelerated the growth (p < 0.05) as well as the microvessel formation (p < 0.01) of transplantation tumor in nude mice. Our study establishes that DDR1 enhances invasion and metastasis of gastric cancer via EMT.
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Significance of oncogenes and tumor suppressor genes in AML prognosis
Abstract
Acute myeloid leukemia (AML) is a heterogeneous disorder among hematologic malignancies. Several genetic alterations occur in this disease, which cause proliferative progression, reducing differentiation and apoptosis in leukemic cells as well as increasing their survival. In the genetic study of AML, genetic translocations, gene overexpression, and mutations effective upon biology and pathogenesis of this disease have been recognized. Proto-oncogenes and tumor suppressor genes, which are important in normal development of myeloid cells, are involved in the regulation of cell cycle and apoptosis, undergo mutation in this type of leukemia, and are effective in prognosis of AML subtypes. This review deals with these genes, the assessment of which can be important in the diagnosis and prognosis of patients as well as therapeutic outcome.
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TUSC3 suppresses glioblastoma development by inhibiting Akt signaling
Abstract
Glioblastoma multiform is one of the most common and most aggressive brain tumors in humans. The molecular and cellular mechanisms responsible for the onset and progression of GBM are elusive and controversial. The function of tumor suppressor candidate 3 (TUSC3) has not been previously characterized in GBM. TUSC3 was originally identified as part of an enzyme complex involved in N-glycosylation of proteins, but was recently implicated as a potential tumor suppressor gene in a variety of cancer types. In this study, we demonstrated that the expression levels of TUSC3 were downregulated in both GBM tissues and cells, and also found that overexpression of TUSC3 inhibits GBM cell proliferation and invasion. In addition, the effects of increased levels of methylation on the TUSC3 promoter were responsible for decreased expression of TUSC3 in GBM. Finally, we determined that TUSC3 regulates proliferation and invasion of GBM cells by inhibiting the activity of the Akt signaling pathway.
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Retrospective multicenter evaluation of patients diagnosed with mucosal melanoma: a study of Anatolian Society of Medical Oncology
Abstract
Mucosal melanoma (MM) is a rare type of cancer that differs significantly from cutaneous melanoma. In this study, we aimed to evaluate clinical and demographical characteristics, prognoses and factors influencing survival, treatment alternatives, and features of different subtypes of the patients. The patients were followed up with and treated in different centers due to their diagnoses of MM. We retrospectively analyzed data of 107 patients who were diagnosed with MM in 14 different institutions in Turkey. The mean age of the patients was 64.5 years. Of the patients, 47 % were female and 53 % were male. The median overall survival (OS) was 17 months, and the mean follow-up duration was 27 months. The 2-year survival rate was 42 %, and the 5-year survival rate was 23 %. The best survival rate appeared in those patients with MM in the head-neck region (median survival rate was 27 months, P = 0.034). The most common anatomical site was the head-neck region. In a univariate analysis, variables including age ≥65 years, the anatomical site of the primary lesion other than head and neck region, the metastatic stage of the disease, high levels of lactate dehydrogenase (LDH), and an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≥1 were found to be associated with poor survival (P < 0.05). However, in a multivariate analysis, only advanced stage disease (HR = 2.70; 95 % CI, 1.64–4.45; P = 0.000) and high LDH levels (HR = 2.31; 95 % CI, 1.40–3.80; P = 0.001) were determined to be adverse prognostic variables. Primary MM presents a more aggressive behavior and offers a poorer prognosis compared to cutaneous melanoma. Because the disease is rarely seen, is heterogeneous, and lacks randomized studies, issues concerning optimal treatment approaches and management and clinical characteristics of the disease have not been clarified yet.
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Plasma exosomal miR-21 and miR-181a differentiates follicular from papillary thyroid cancer
Abstract
Thyroid cancer (TC) is the most common endocrine malignancy and its incidence has increased over the last few decades. As has been revealed by a number of studies, TC tissue's micro-RNA (miRNA) profile may reflect histological features and the clinical behavior of tumor. However, alteration of the miRNA profile of plasma exosomes associated with TC development has to date not been explored. We isolated exosomes from plasma and assayed their characteristics using laser diffraction particle size analysis, atomic force microscopy, and western blotting. Next, we profiled cancer-associated miRNAs in plasma exosomes obtained from papillary TC patients, before and after surgical removal of the tumor. The diagnostic value of selected miRNAs was evaluated in a large cohort of patients displaying different statuses of thyroid nodule disease. MiRNA assessment was performed by RT-qPCR. In total, 60 patients with different types of thyroid nodal pathology were included in the study. Our results revealed that the development of papillary TC is associated with specific changes in exosomal miRNA profiles; this phenomenon can be used for differential diagnostics. MiRNA-31 was found to be over-represented in the plasma exosomes of patients with papillary TC vs. benign tumors, while miRNA-21 helped to distinguish between benign tumors and follicular TC. MiRNA-21 and MiRNA-181a-5p were found to be expressed reciprocally in the exosomes of patients with papillary and follicular TC, and their comparative assessment may help to distinguish between these types of TC with 100 % sensitivity and 77 % specificity.
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miR-96 promotes the growth of prostate carcinoma cells by suppressing MTSS1
Abstract
Prostate carcinoma (PC) is one of the most common cancers for males. However, the molecular mechanisms of PC progression are still to be uncovered. MicroRNA (miRNA) has been shown to be associated with the initiation and progression of prostate cancer. Among the identified tumor-promoting miRNAs, miR-96 has been well established to contribute to PC by reducing FOXO1 expression. This study is aimed to study if miR-96 can promote the progression of PC through other pathways. Our data reinforced the finding that the level of miR-96 was higher in PC samples and cell lines than in non-cancerous tissues and normal prostate epithelial cells. In addition, serum miR-96 abundance was also found to be elevated in PC patients. Decreasing miR-96 expression was able to suppress the proliferation, clonogenicity, and invasion of PC cells. Overexpressing miR-96 led to increased proliferation and colony formation of normal prostate epithelial cells. miR-96 level was found to be inversely associated with the abundance of metastasis suppressor protein 1 (MTSS1) messenger RNA (mRNA), which has been proved to be a tumor suppressor for PC. Predictive analysis indicated that there was a potential miRNA response elements (MREs) located within 3′UTR of MTSS1 mRNA. The changes in miR-96 expression can affect the levels of MTSS1 both at mRNA and protein levels. miR-96 also suppressed the activity of luciferase reporter under the regulation of 3′UTR of MTSS1. Further studies showed that MTSS1 restoration accounted for the effect of miR-96 reduction on PC cells. The overexpression of a recombinant MTSS1 resistant against miRNA regulation was also demonstrated to abolish the transforming effect of miR-96 on prostate epithelial cells. Taken together, we found that miR-96 has a higher abundance in serum samples of PC patients than healthy controls, implying that it may be used as a prognostic marker. MTSS1 is a new authentic target of miR-96 in PC. The above findings suggested that targeting miR-96 may be a promising strategy for PC treatment.
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Genetic analysis of radiation-specific biomarkers in sinonasal squamous cell carcinomas
Abstract
The aim of this study was to investigate the differences in the gene expression profiles of radiation-sensitive (RS) and radiation-resistant (RR) sinonasal squamous cell carcinoma (SNSCC) and to identify prognostic markers for the radiation reaction of SNSCC. We first examined the differentially expressed genes (DEGs) in RS and RR SNSCC tissues by analyzing clinical samples with GeneChip Human Transcriptome Array 2.0 (HTA 2.0).To understand the functional significance of the molecular changes, we examined the DEGs with Gene Ontology (GO) and pathway analyses to identify the core genes. The expression of several core genes (CCND2, COL5A2, GADD45B, and THBS2) was confirmed with reverse transcription quantitative PCR (RT-qPCR) in a larger series of tissues. We identified 208 DEGs, of which 76 were upregulated and 132 downregulated in the RS tissues relative to the RR tissues. The DEGs were mainly involved in the regulation of cell proliferation, the NF-kappaB signaling pathway, the cell adhesion molecule signaling pathway, and the extracellular matrix–receptor interaction signaling pathway. RT-qPCR confirmed that the CCND2, COL5A2, GADD45B, and THBS2 genes were significantly differentially expressed in the RS and RR tissues, consistent with the GeneChip data. These results extend our understanding of the molecular mechanisms underlying the sensitivity of SNSCC to radiation. The DEGs are involved in the differential response to radiation therapy and the dysregulated core genes identified in this study can be used to predict radiation sensitivity in SNSCC.
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A phase II experience evaluating quality of life and survival in linac-based SBRT for prostate cancer
Abstract
Objective
This study aims to evaluate SBRT with volumetric modulated arc therapy (VMAT) and toxicity using five validated quality of life (QOL) instruments.
Methods
An approved prospective NCI-designated phase II study (NCT01581749) was conducted. The inclusion criteria are the following: histologically proven prostate adenocarcinoma, Gleason score 6–7, clinical stage T1b-T2b, PSA ≤20 ng/ml, prostate volume ≤100 cm3, and no prior prostate radiotherapy. SBRT was delivered as 36.25 Gy in five fractions to PTV via VMAT. Patients self-reported on validated QOL measures including the American Urological Association (AUA) Index, Sexual Health Inventory for Men (SHIM), Utilization of Sexual Medications/Devices (USMD), and Expanded Prostate Cancer Index Composite Short Form (EPIC-26). In addition, PSA response and survival were evaluated.
Results
A total of 33 patients were entered into the study. Median time from treatment to last follow up was 30 months. Mean age was 67.5 years. Mean PSA was 6.1 and Gleason scores ranged from 6 to 7. Mean PSA declined by 42 % was observed at 1 month post-treatment and continued to decrease. Three patients (9.7 %) had PSA bounce, with one patient having disease progression (3.0 %). There were no transient side effects or sequelae noted on their QOL questionnaires over the follow-up period of 36 months. Some adverse effects to sexual health were noticed with the majority of these incidences occurring within 1 month after treatment and resolved within 3 months of symptom onset.
Conclusion
SBRT with VMAT for low-intermediate risk prostate cancer is well tolerated. Acute toxicities showed no apparent impact on patient general sense of well-being. No adverse effects were observed over the 36 month period.
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The aurora kinase inhibitor VX-680 shows anti-cancer effects in primary metastatic cells and the SW13 cell line
Abstract
New therapeutic targets are needed to fight cancer. Aurora kinases (AK) were recently identified as vital key regulators of cell mitosis and have consequently been investigated as therapeutic targets in preclinical and clinical studies. Aurora kinase inhibitors (AKI) have been studied in many cancer types, but their potential capacity to limit or delay metastases has rarely been considered, and never in adrenal tissue. Given the lack of an effective pharmacological therapy for adrenal metastasis and adrenocortical carcinoma, we assessed AKI (VX-680, SNS314, ZM447439) in 2 cell lines (H295R and SW13 cells), 3 cell cultures of primary adrenocortical metastases (from lung cancer), and 4 primary adrenocortical tumor cell cultures. We also tested reversan, which is a P-gp inhibitor (a fundamental efflux pump that can extrude drugs), and we measured AK expression levels in 66 adrenocortical tumor tissue samples. Biomolecular and cellular tests were performed (such as MTT, thymidine assay, Wright's staining, cell cycle and apoptosis analysis, Western blot, qRT-PCR, and mutation analysis). Our results are the first to document AK overexpression in adrenocortical carcinoma as well as in H295R and SW13 cell lines, thus proving the efficacy of AKI against adrenal metastases and in the SW13 cancer cell model. We also demonstrated that reversan and AKI Vx-680 are useless in the H295R cell model, and therefore should not be considered as potential treatments for ACC. Serine/threonine AK inhibition, essentially with VX-680, could be a promising, specific therapeutic tool for eradicating metastases in adrenocortical tissue.
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Transfer of malignant trait to BRCA1 deficient human fibroblasts following exposure to serum of cancer patients
Abstract
Background
It was reported that metastases might occur via transfer of biologically active blood circulating molecules from the primary tumor to distant organs rather than only migration of cancer cells. We showed in an earlier study that exposure of immortalized human embryonic kidney cells (HEK 293) to cancer patient sera, induce their transformation into undifferentiated cancers due to a horizontal transfer of malignant traits. In the present work, we tested the hypothesis that even other human cells as long as they are deficient for a single oncosuppressor gene might undergo malignant transformation when exposed to human cancer serum.
Methods
We used the CRISPR/Cas9 system to establish a stable BRCA1 knockout (KO) in human fibroblasts. The BRCA1-KO fibroblasts were exposed to cancer patients' sera or healthy patients' sera for 2 weeks. Treated cells were analyzed for cell proliferation and transformation to study their susceptibility to the oncogenic potential of cancer patients' sera and to determine the possible mechanisms underlying their hypothesized transformation.
Results
BRCA1-KO fibroblasts treated with cancer patients' sera displayed higher proliferation and underwent malignant transformation as opposed to wild type control fibroblasts, which were not affected by exposure to cancer patients' sera. The malignant transformation was not seen when BRCA1-KO fibroblasts were treated with healthy human sera. Histological analysis of tumors generated by BRCA1-KO fibroblasts showed that they were carcinomas with phenotypical characteristics related to the cancers of the blood donor patients. Interestingly, BRCA1-KO fibroblasts were significantly more prone to internalize serum-derived exosomes, when compared to wild type fibroblasts. This suggests that oncosuppressor genes might protect the integrity of the cell genome also by blocking integration of cancer-derived exosomes.
Conclusion
These data support the hypothesis that any human cells carrying a single oncosuppressor mutation is capable of integrating cancer factors carried in the blood and undergo complete malignant transformation. Oncosuppressor genes might protect the cell genome by impeding the integration inside the cells of these mutating factors.
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Significance of oncogenes and tumor suppressor genes in AML prognosis
Abstract
Acute myeloid leukemia (AML) is a heterogeneous disorder among hematologic malignancies. Several genetic alterations occur in this disease, which cause proliferative progression, reducing differentiation and apoptosis in leukemic cells as well as increasing their survival. In the genetic study of AML, genetic translocations, gene overexpression, and mutations effective upon biology and pathogenesis of this disease have been recognized. Proto-oncogenes and tumor suppressor genes, which are important in normal development of myeloid cells, are involved in the regulation of cell cycle and apoptosis, undergo mutation in this type of leukemia, and are effective in prognosis of AML subtypes. This review deals with these genes, the assessment of which can be important in the diagnosis and prognosis of patients as well as therapeutic outcome.
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Pseudoprogression in children, adolescents and young adults with non-brainstem high grade glioma and diffuse intrinsic pontine glioma
Abstract
Pseudoprogression (PsP) is a treatment-related phenomenon which hinders response interpretation. Its prevalence and clinical impact have not been evaluated in children/adolescents. We assessed the characteristics, risk factors and prognosis of PsP in children/adolescents and young-adults diagnosed with non-brainstem high grade gliomas (HGG) and diffuse intrinsic pontine gliomas (DIPG). Patients aged 1–21 years diagnosed with HGG or DIPG between 1995 and 2012 who had completed radiotherapy were eligible. PsP was assessed according to study-specific criteria and correlated with first-line treatment, molecular biomarkers and survival. Ninety-one patients (47 HGG, 44 DIPG) were evaluable. Median age: 10 years (range, 2–20). Eleven episodes of PsP were observed in 10 patients (4 HGG, 6 DIPG). Rates of PsP: 8.5 % (HGG); 13.6 % (DIPG). Two episodes of PsP were based on clinical findings alone; nine episodes had concurrent radiological changes: increased size of lesions (n = 5), new focal enhancement (n = 4). Temozolomide, MGMT methylation or H3F3A mutations were not found to be associated with increased occurrence of PsP. For HGG, 1-year progression-free survival (PFS) was 41.9 % no-PsP versus 100 % PsP (p = 0.041); differences in 1-year overall survival (OS) were not significant. For DIPG, differences in 1-year PFS and OS were not statistically significant. Hazard ratio (95 %CI) of PsP for OS was 0.551 (0.168–1.803; p = 0.325) in HGG; and 0.308 (0.107–0.882; p = 0.028) in DIPG. PsP occurred in both pediatric HGG and DIPG patients at a comparable rate to adult HGG. PsP was associated with improved 1-yr PFS in HGG patients. PsP had a protective effect upon OS in DIPG patients.
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Regression standardization with the R package stdReg
Abstract
When studying the association between an exposure and an outcome, it is common to use regression models to adjust for measured confounders. The most common models in epidemiologic research are logistic regression and Cox regression, which estimate conditional (on the confounders) odds ratios and hazard ratios. When the model has been fitted, one can use regression standardization to estimate marginal measures of association. If the measured confounders are sufficient for confounding control, then the marginal association measures can be interpreted as poulation causal effects. In this paper we describe a new R package, stdReg, that carries out regression standardization with generalized linear models (e.g. logistic regression) and Cox regression models. We illustrate the package with several examples, using real data that are publicly available.
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Quantifying the changes in survival inequality for Indigenous people diagnosed with cancer in Queensland, Australia
Publication date: August 2016
Source:Cancer Epidemiology, Volume 43
Author(s): Peter D. Baade, Paramita Dasgupta, Paul W. Dickman, Susanna Cramb, John D. Williamson, John R. Condon, Gail Garvey
The survival inequality faced by Indigenous Australians after a cancer diagnosis is well documented; what is less understood is whether this inequality has changed over time and what this means in terms of the impact a cancer diagnosis has on Indigenous people. Survival information for all patients identified as either Indigenous (n=3168) or non-Indigenous (n=211,615) and diagnosed in Queensland between 1997 and 2012 were obtained from the Queensland Cancer Registry, with mortality followed up to 31st December, 2013. Flexible parametric survival models were used to quantify changes in the cause-specific survival inequalities and the number of lives that might be saved if these inequalities were removed. Among Indigenous cancer patients, the 5-year cause-specific survival (adjusted by age, sex and broad cancer type) increased from 52.9% in 1997–2006 to 58.6% in 2007–2012, while it improved from 61.0% to 64.9% among non-Indigenous patients. This meant that the adjusted 5-year comparative survival ratio (Indigenous: non-Indigenous) increased from 0.87 [0.83–0.88] to 0.89 [0.87–0.93], with similar improvements in the 1-year comparative survival. Using a simulated cohort corresponding to the number and age-distribution of Indigenous people diagnosed with cancer in Queensland each year (n=300), based on the 1997–2006 cohort mortality rates, 35 of the 170 deaths due to cancer (21%) expected within five years of diagnosis were due to the Indigenous: non-Indigenous survival inequality. This percentage was similar when applying 2007–2012 cohort mortality rates (19%; 27 out of 140 deaths). Indigenous people diagnosed with cancer still face a poorer survival outlook than their non-Indigenous counterparts, particularly in the first year after diagnosis. The improving survival outcomes among both Indigenous and non-Indigenous cancer patients, and the decreasing absolute impact of the Indigenous survival disadvantage, should provide increased motivation to continue and enhance current strategies to further reduce the impact of the survival inequalities faced by Indigenous people diagnosed with cancer.
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Transfer of malignant trait to BRCA1 deficient human fibroblasts following exposure to serum of cancer patients
It was reported that metastases might occur via transfer of biologically active blood circulating molecules from the primary tumor to distant organs rather than only migration of cancer cells. We showed in an ...
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Iodine Uptake Patterns on Post-ablation Whole Body Scans are Related to Elevated Serum Thyroglobulin Levels After Radioactive Iodine Therapy in Patients with Papillary Thyroid Carcinoma
Abstract
Purpose
Serum thyroglobulin (Tg) level is frequently elevated shortly after radioactive iodine (RAI) ablation therapy. The authors studied the relationship between the elevation of serum Tg after RAI therapy and iodine uptake pattern on post-ablation whole body scans (RxWBSs) in patients with papillary thyroid carcinoma (PTC).
Materials and Methods
The study subjects were patients with PTC that had undergone first RAI therapy with thyroid hormone withdrawal after total thyroidectomy. Patients with a high level of serum anti-Tg antibody (TgAb, ≥ 60 U/mL), possible regional or distant metastasis as determined by pre-ablation or post-ablation studies, and negative iodine uptake of the anterior neck on RxWBS were excluded. Serum Tg was checked twice, that is, 7 days after (post-ablation Tg) and on the day of RAI therapy (pre-ablation Tg). Ratio of pre-ablation Tg to post-ablation Tg (Tg ratio) was used to assess changes in serum Tg levels after RAI therapy. Patients were classified into two groups according to the presence of midline uptake above the thyroidectomy bed on RxWBS (negative (group 1) or positive (group 2) midline uptake). Variables were subjected to analysis to identify differences between the two groups.
Results
Two hundred and fifty patients were enrolled in this study; 101 in group 1 and 149 in group 2. Based on univariate analysis, post-ablation Tg (8.12 ± 11.05 vs. 34.12 ± 54.31; P < 0.001) and Tg ratio (7.81 ± 8.98 vs. 20.01 ± 19.84; P < 0.001) were significantly higher in group 2. On the other hand, gender, tumor (T) stage, lymph node (N) stage, size, multiplicity or bilaterality of primary tumor, dose of 131I, serum TgAb and thyroid-stimulating hormone (TSH) level (before or after RAI therapy) were not significantly different in the two groups. Variables with P values of < 0.25 by univariate analysis were subjected to multivariate analysis, which showed post-ablation Tg (OR 1.060, 95 % CI = 1.028–1.092; P < 0.001) and Tg ratio (OR 1.059, 95 % CI = 1.028–1.092; P = 0.001) were significantly higher in group 2.
Conclusion
Serum Tg level after RAI therapy was significantly higher in patients with midline uptake on RxWBS, compared with patients without midline uptake on RxWBS. Further investigations are needed to reveal the correlation between serum Tg elevation and clinical outcome according to the presence of midline uptake.
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DDR1 enhances invasion and metastasis of gastric cancer via epithelial-mesenchymal transition
Abstract
In this study, we investigated the effects of DDR1 on the invasion and metastasis in gastric cancer (GC) via epithelial-mesenchymal transition (EMT). Immunohistochemistry analysis was used to detect DDR1, E-cadherin, and Vimentin expression in GC tissues as well as DDR1 expression in GC cell lines and normal gastric epithelial cells. The relationship between DDR1 expression and EMT in GC cell lines was explored by down and upregulating DDR1 and examining corresponding changes in the expression of EMT-related proteins and in biological characteristics. Furthermore, a nude mice model with a transplantation tumor generating from stably transfected GC cells with DDR1 overexpression was established and performed to further reveal the effects of DDR1 expression on cellular morphology and growth of GC. Our results showed that DDR1 was highly expressed in GC tissues and cell lines compared with adjacent tissues and normal cell line, and its expression was significantly higher in GC having poor differentiation (p < 0.01), advanced depth of wall invasion (p = 0.020), lymph node metastasis (p = 0.0001), liver metastasis (p < 0.01), and high TNM stage (p < 0.01). Western blot analyses revealed that DDR1 overexpression resulted in a significant decrease in the expression of E-cadherin (p < 0.01) and an increase in the expression of Vimentin and Snail (p < 0.01), while knockdown of DDR1 led to opposite outcomes. We further demonstrated that DDR1 overexpression promoted GC cell proliferation (p < 0.05), migration (p < 0.01), and invasion (p < 0.01), and accelerated the growth (p < 0.05) as well as the microvessel formation (p < 0.01) of transplantation tumor in nude mice. Our study establishes that DDR1 enhances invasion and metastasis of gastric cancer via EMT.
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Early Switch in Tyrosine Kinase Inhibitor Therapy for Patients With Chronic Myeloid Leukemia: An Emerging Clinical Question
Publication date: Available online 14 May 2016
Source:Critical Reviews in Oncology/Hematology
Author(s): Kendra Sweet, Javier Pinilla-Ibarz
Response to frontline BCR-ABL1-targeted tyrosine kinase inhibitor (TKI) therapy is associated with an improved prognosis for patients with chronic myeloid leukemia (CML). Accordingly, the National Comprehensive Cancer Network (NCCN) and European LeukemiaNet (ELN) recommend the use of specific response milestones (eg, BCR-ABL1≤10% on the International Scale at 3 months) to assess treatment success and inform follow-up care, including potentially switching to another TKI therapy. However, prior to any treatment change, the potential benefits and risks of each TKI and the goals of the patient must be considered. Here we review current NCCN and ELN response recommendations for patients with CML, highlight the impact of early responses on long-term prognosis, and discuss several reasons patients may consider a switch in TKI therapy. We also review completed and ongoing clinical studies involving a switch in frontline therapy for patients with CML, including those with a treatment-free remission phase.
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Clinical significance of microRNAs in chronic and acute human leukemia
Abstract
Small non-coding microRNAs (miRNAs) are epigenetic regulators that target specific cellular mRNA to modulate gene expression patterns and cellular signaling pathways. miRNAs are involved in a wide range of biological processes and are frequently deregulated in human cancers. Numerous miRNAs promote tumorigenesis and cancer progression by enhancing tumor growth, angiogenesis, invasion and immune evasion, while others have tumor suppressive effects (Hayes, et al., Trends Mol Med 20(8): 460–9, 2014; Stahlhut and Slack, Genome Med 5 (12): 111, 2013). The expression profile of cancer miRNAs can be used to predict patient prognosis and clinical response to treatment (Bouchie, Nat Biotechnol 31(7): 577, 2013). The majority of miRNAs are intracellular localized, however circulating miRNAs have been detected in various body fluids and represent new biomarkers of solid and hematologic cancers (Fabris and Calin, Mol Oncol 10(3):503–8, 2016; Allegra, et al., Int J Oncol 41(6): 1897–912, 2012). This review describes the clinical relevance of miRNAs, lncRNAs and snoRNAs in the diagnosis, prognosis and treatment response in patients with chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML) and acute adult T-cell leukemia (ATL).
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State of affairs in use of steroids in diffuse intrinsic pontine glioma: an international survey and a review of the literature
Abstract
Children diagnosed with diffuse intrinsic pontine glioma (DIPG) face a dismal prognosis, with severe neurologic deterioration and inevitable death at a median of 9 months from diagnosis. Steroids are widely prescribed as supportive or palliative treatment although they are known to cause severe side effects that may reduce the quality of life. This study aims to review the current knowledge on, and use of, steroids in DIPG patients. A global questionnaire-study among health care professionals was performed to ascertain information on the current (multi-)institutional and (multi-)national use of steroids, the availability of clinical guidelines, and the need for improvements in prescribing steroids to DIPG patients. In addition, an extensive literature search was performed to review studies investigating steroids in pediatric brain tumor patients. From 150 responding health care professionals, only 7 % had clinical guidelines. The use of steroids was heterogeneous and over 85 % of respondents reported serious side effects. Fourteen articles, with low level of evidence, described the use of steroids in pediatric brain tumor patients. Clinical trials investigating optimal dose or regimen were lacking. This study is a first inventory of the availability of evidence-based information and clinical guidelines, and the current attitude towards the use of steroids in DIPG patients. To date, the risk–benefit ratio of steroids in this disease is yet to be determined. We emphasize the need for clinical trials resulting in guidelines on steroids, and possibly alternative drugs, to optimize the quality of care and quality of life of DIPG patients.
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An allograft mouse model for the study of hearing loss secondary to vestibular schwannoma growth
Abstract
Vestibular schwannoma is a benign neoplasm arising from the Schwann cell sheath of the auditory-vestibular nerve. It most commonly affects both sides in the genetic condition Neurofibromatosis type 2, causing progressive high frequency sensorineural hearing loss. Here, we describe a microsurgical technique and stereotactic coordinates for schwannoma cell grafting in the vestibular nerve region that recapitulates local tumor growth in the cerebellopontine angle and inner auditory canal with resulting hearing loss. Tumor growth was monitored by bioluminescence and MRI in vivo imaging, and hearing assessed by auditory brainstem responses. These techniques, by potentially enabling orthotopic grafting of a variety of cell lines will allow studies on the pathogenesis of tumor-related hearing loss and preclinical drug evaluation, including hearing endpoints, for NF2-related and sporadic schwannomas.
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RECIST 1.1—Update and clarification: From the RECIST committee
Publication date: Available online 14 May 2016
Source:European Journal of Cancer
Author(s): Lawrence H. Schwartz, Saskia Litière, Elisabeth de Vries, Robert Ford, Stephen Gwyther, Sumithra Mandrekar, Lalitha Shankar, Jan Bogaerts, Alice Chen, Janet Dancey, Wendy Hayes, F. Stephen Hodi, Otto S. Hoekstra, Erich P. Huang, Nancy Lin, Yan Liu, Patrick Therasse, Jedd D. Wolchok, Lesley Seymour
The Response Evaluation Criteria in Solid Tumours (RECIST) were developed and published in 2000, based on the original World Health Organisation guidelines first published in 1981. In 2009, revisions were made (RECIST 1.1) incorporating major changes, including a reduction in the number of lesions to be assessed, a new measurement method to classify lymph nodes as pathologic or normal, the clarification of the requirement to confirm a complete response or partial response and new methodologies for more appropriate measurement of disease progression. The purpose of this paper was to summarise the questions posed and the clarifications provided as an update to the 2009 publication.
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Combinatory effect of BRCA1 and HERC2 expression on outcome in advanced non-small-cell lung cancer
Abstract
Background
BRCA1 is a main component of homologous recombination and induces resistance to platinum in preclinical models. It has been studied as a potential predictive marker in lung cancer. Several proteins modulate the function of BRCA1. The E3 ubiquitin ligase HERC2 facilitates the assembly of the RNF8-UBC13 complex to recruit BRCA1 to DNA damage sites. The combined analysis of multiple components of the pathway leading to the recruitment of BRCA1 at DNA damage sites has the potentiality to improve the BRCA1 predictive model.
Methods
We retrospectively analyzed 71 paraffin-embedded tumor samples from advanced non-small-cell lung cancer patients treated with first-line platinum based chemotherapy and measured the mRNA expression levels of BRCA1, RNF8, UBC13 and HERC2 using real-time PCR. The mRNA expression was categorized using median value as cut-off point.
Results
The median progression-free survival of all 71 patients was 7.2 months whereas the median overall survival of the study population was 10.7 months. Among patients with low BRCA1 expression, the median PFS was 7.4 months in the presence of low HERC2 levels and 5.9 months for patients expressing high HERC2 levels (p = 0.01). The median OS was 15.3 months for patients expressing low levels of both genes and 7.4 months for those with low BRCA1 but high HERC2 (p = 0.008). The multivariate analysis showed that among patients with Eastern Cooperative Oncology Group performance status 0–1, the combined low expression of both BRCA1 and HERC2 clearly reduced the risk of progression (p = 0.03) and of death (p = 0.004).
Conclusions
These findings confirm the potentiality of integrated DNA repair components analysis in predicting the sensitivity to platinum in lung cancer. The study indicates a predictive role for HERC2 mRNA expression and paves the way for further refinement of the BRCA1 predictive model.
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Smoking-related cancer in military veterans: retrospective cohort study of 57,000 veterans and 173,000 matched non-veterans
Abstract
Background
Serving military personnel are more likely to smoke, and to smoke more heavily, than civilians. The aim of our study was to examine whether veterans have an increased risk of a range of smoking-related cancers compared with non-veterans, using a large, national cohort of veterans.
Methods
We conducted a retrospective cohort study of 57,000 veterans resident in Scotland and 173,000 age, sex and area of residence matched civilians. We used Cox proportional hazard models to compare the risk of any cancer, lung cancer and other smoking-related cancers overall, by sex and by birth cohort, adjusting for the potential confounding effect of socioeconomic deprivation.
Results
Over a mean of 29 years follow-up, 445 (0.79 %) veterans developed lung cancer compared with 1106 (0.64 %) non-veterans (adjusted hazard ratio 1.16, 95 % confidence intervals 1.04–1.30, p = 0.008). Other smoking-related cancers occurred in 737 (1.31 %) veterans compared with 1883 (1.09 %) non-veterans (adjusted hazard ratio 1.18, 95 % confidence intervals 1.08–1.29, p < 0.001). A significantly increased risk was observed among veterans born 1950–1954 for lung cancer and 1945–1954 for other smoking-related cancers. The risk of lung cancer was decreased among veterans born 1960 onwards. In comparison, there was no difference in the risk of any cancer overall (adjusted hazard ratio 0.98, 95 % confidence intervals 0.94–1.01, p = 0.171), whilst younger veterans were at reduced risk of any cancer (adjusted hazard ratio 0.88, 95 % confidence intervals 0.81–0.97, p = 0.006).
Conclusions
Military veterans living in Scotland who were born before 1955 are at increased risk of smoking-related cancer compared with non-veterans, but younger veterans are not. The differences may reflect changing patterns of smoking behaviour over time in military personnel which may, in turn, be linked to developments in military health promotion policy and a changing military operational environment, as well as to wider societal factors.
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A simulation model of microsphere distribution for selective internal radiation therapy agrees with observations
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Jonas Högberg, Magnus Rizell, Ragnar Hultborn, Johanna Svensson, Olof Henrikson, Johan Mölne, Peter Gjertsson, Peter Bernhardt
PurposeLarge clusters of resin microspheres are common in normal liver tissue arteries after selective internal radiation therapy, which might lead to pronounced heterogeneity in the absorbed dose distribution. To describe microsphere-clustering properties, we constructed a hepatic artery branching tree model and tested it against biopsy findings.MethodsOur virtual model consisted of arteries that successively branched into two new generations of arteries at 20 nodes. The artery diameter exponentially decreased from the lowest generation to the highest generation. Three variable parameters were optimised to obtain concordance between simulations and measure microsphere distributions: an artery coefficient of variation (ACV) for the diameter of all artery generations and the microsphere flow distribution at the nodes; a hepatic tree distribution volume (HDV) for the artery tree; and an artery diameter reduction (ADR) parameter. The model was tested against previously measured activity concentrations in 84 biopsies from the liver of one patient. In 16/84 biopsies, the microsphere distribution regarding cluster size and localisation in the artery tree was determined via light microscopy of 30-μm sections (mean concentration, 14 microspheres/mg; distributions divided into three groups with mean microsphere concentrations of 4.6, 14, and 28 microspheres/mg).ResultsSingle spheres and small clusters were observed in terminal arterioles while large clusters, up to 450 microspheres, were observed in larger arterioles. For 14 microspheres/mg, the optimised parameter values were ACV=0.35, HDV=50 cm3, and ADR=6 μm. For 4.6 microspheres/mg, ACV and ADR decreased to 0.26 and 0 μm, respectively, while HDV increased to 130 cm3. The opposite trend was observed for 28 microspheres/mg: ACV=0.49, HDV=20 cm3, and ADR=8 μm.ConclusionSimulations and measurements reveal that microsphere clusters are larger and more common in volumes with high microsphere concentrations and indicate that the spatial distribution of the artery tree must be considered in estimates of microsphere distributions.
Teaser
Microsphere clusters are common in normal liver tissue arteries after radioembolisation. To describe microsphere-clustering properties, we analysed the microsphere distribution in patient biopsies and constructed a hepatic artery branching tree model that successively branched into two new generations of arteries at 20 nodes. In agreement with the clinical findings, simulations revealed that microsphere clusters are larger and more common in volumes with high microsphere concentrations than has been previously predicted.from Cancer via ola Kala on Inoreader http://ift.tt/1TMYtWA
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Reduced mortality with partial breast irradiation for early breast cancer – a meta-analysis of randomised trials
Publication date: Available online 13 May 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Jayant S. Vaidya, Max Bulsara, Frederik Wenz, Nathan Coombs, Julian Singer, Stephen Ebbs, Samuele Massarut, Christobel Saunders, Michael Douek, Norman Williams, David Joseph, Jeffrey S. Tobias, Michael Baum
BackgroundWith earlier detection and more effective treatment, mortality from breast cancer continues to fall and it has become increasingly important to reduce the toxicity of treatments. Partial breast radiotherapy, which focuses radiation to the tumour bed may achieve this aim. We analysed mortality differences in randomised trials of partial breast irradiation.MethodWe included data from published randomized trials of partial breast irradiation (alone or as part of a risk-adapted approach) vs. whole breast irradiation for invasive breast cancer suitable for breast conservation therapyWe identified trials using Pubmed and Google search with the terms "partial breast irradiation" OR "intraoperative radiotherapy" OR "IMRT" OR ("accelerated" AND "radiation") AND "randomised / randomized", and as well as through discussion with colleagues in the field. We calculated the proportion of patients who had events in each randomised arm at 5 years follow up and created a Forest plot using STATA version 14.1.ResultsWe identified 9 randomised trials of PBI vs. WBI in invasive breast cancer; 5-year outcomes were available for non-breast-cancer mortality in 5 trials (n=4489) and for breast-cancer mortality in 4 trials (n=4231). The overall mortality was 4.9%. There was no detectable heterogeneity between the trials for any of the outcomes.There was no difference in proportion of patients dying from breast cancer (difference 0.000% (95% CI -0.7 to +0.7), p=0.999). Non-breast cancer mortality with PBI was lower than WBI (difference 1.1% (95% CI -2.1% to -0.2%), p=0.023). Total mortality with PBI was also lower than WBI (difference 1.3% (95%CI -2.5% – 0.0%), p=0.05).ImplicationsUse of PBI instead of WBI in selected patients results in a lower 5-year non-breast-cancer and overall mortality, amounting to a 25% reduction in relative terms. This information should be included when breast conserving therapy is proposed to a patient.
Teaser
Our meta-analysis of 5-year data from published randomized trials of partial breast irradiation (PBI, alone or within a risk-adapted approach) vs. whole breast irradiation (WBI) for invasive breast cancer treated with lumpectomy, found no difference in breast cancer mortality (n=4489,difference 0.000%(95%CI -0.7 to +0.7),p=0.972). PBI was better than WBI for non-breast cancer mortality (n=4231,difference 1.1% (95%CI -2.1% to -0.2%),p=0.023), and total mortality (difference 1.3% (95%CI -2.5% – 0.0%),p=0.05), leading to a 25% relative risk reduction.from Cancer via ola Kala on Inoreader http://ift.tt/24ZqENw
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Heat Inactivation of Garlic (Allium sativum) Extract Abrogates Growth Inhibition of HeLa Cells.
Heat Inactivation of Garlic (Allium sativum) Extract Abrogates Growth Inhibition of HeLa Cells.
Nutr Cancer. 2016 May 13;:1-9
Authors: Chintapalli R, Murray MJ, Murray JT
Abstract
The potential anticancer properties of garlic (Allium sativum) may depend on the method of preparation and its storage. Storage of garlic has not been thoroughly investigated to determine whether anticancer properties are retained. Garlic was prepared and processed to mimic normal options for storage and preparation for consumption. Cytotoxicity was determined by crystal violet assay and mechanisms of cytotoxicity were established by microscopy, SDS-PAGE, and Western immunoblotting. Significant (P < 0.0001) cytotoxicity was observed in all preparations, except with boiled (cooked) garlic. Depending on the method of storage, garlic extract induced either type I or type II programmed cell death, detectable by caspase 9 cleavage, or Poly (adenosine diphosphate-ribose) polymerase (PARP) cleavage and LC3-II accumulation, respectively. The conflicting literature on the anticancer properties of garlic may be explained by differences in processing and storage. This study has highlighted that the potency of the antiproliferative properties of cooked garlic, compared to the uncooked form, is diminished in HeLa cells.
PMID: 27176674 [PubMed - as supplied by publisher]
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Early Life and Postnatal Western Diet Feeding and Susceptibility to Chemically Induced Colonic Aberrant Crypt Foci in Male Rats Offspring.
Early Life and Postnatal Western Diet Feeding and Susceptibility to Chemically Induced Colonic Aberrant Crypt Foci in Male Rats Offspring.
Nutr Cancer. 2016 May 13;:1-7
Authors: Lopes GA, Dias MC, Barbisan LF, Marchesan Rodrigues MA
Abstract
The modifying effects of a Western diet (WD) during early life on the susceptibility to colon carcinogenesis induced by dimethylhydrazine (DMH) were examined in male rats as later adults. Three groups were studied: a lifetime control diet-fed group, a test group fed WD since pregnancy from dams until postnatal day (PND) 42, and a group fed WD at adulthood. At PND 70, all groups received the carcinogen DMH and were euthanized 10 wk later. Colonic aberrant crypt foci (ACF) were scored (number and crypt multiplicity) and the altered pattern of β-catenin expression was evaluated in the colonic lesions. ACF multiplicity (≥4 crypts) was significantly higher in the group fed WD at early life than in the group fed the control diet. ACF number, crypt multiplicity, and the number of high-grade dysplastic lesions were significantly higher in the group fed WD at adulthood than in the groupfed the control diet. The number of lesions with altered β-catenin expression was higher in the groups receiving WD at early life or at adulthood than in the lifetime control-diet-fed group. These findings indicate that WD exposure at early life increased the susceptibility to colon carcinogenesis at adulthood.
PMID: 27176572 [PubMed - as supplied by publisher]
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A Pilot Study of Self-Management-based Nutrition and Physical Activity Intervention in Cancer Survivors.
A Pilot Study of Self-Management-based Nutrition and Physical Activity Intervention in Cancer Survivors.
Nutr Cancer. 2016 May 13;:1-10
Authors: Miller M, Zrim S, Lawn S, Woodman R, Leggett S, Jones L, Karapetis C, Kichenadasse G, Sukumaran S, Roy AC, Koczwara B
Abstract
Exercise and a healthy diet are beneficial after cancer, but are not uniformly adopted by cancer survivors. This study reports on the feasibility, acceptability, and effectiveness of a self-management-based nutrition and exercise intervention for Australian cancer survivors. Adult survivors (n = 25) during curative chemotherapy (stratum 1[S1]; n = 11) or post-treatment (stratum 2 [S2]; n = 14) were recruited prospectively from a single center. The Flinders Living Well Self-Management Program™ (FLW Program) was utilized to establish patient-led nutrition and exercise goals and develop a tailored 12-wk intervention plan. Fortnightly reviews occurred with assessments at baseline, 6 and 12 wk. A recruitment and retention rate of 38% and 84% were observed. Both strata maintained total skeletal muscle mass. Small reductions in body mass index, hip circumference, and percentage body fat, and small increases in hand grip strength and exercise capacity among subjects in both strata were observed. No significant differences were observed between strata; however, significant increases in exercise capacity and global health status for S2 were observed from baseline to 12 wk. FLW Program is a feasible mode of delivering nutrition and exercise intervention to cancer survivors and it appears that there are no barriers to implementing this program early during chemotherapy. Hence, the additive effect of gains achieved over a longer duration is promising and this should be explored in randomized controlled trials adequately powered to observe clinically and statistically significant improvements in relevant outcomes.
PMID: 27176450 [PubMed - as supplied by publisher]
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Folic Acid Supplementation Adversely Affects Chemosensitivity of Colon Cancer Cells to 5-fluorouracil.
Folic Acid Supplementation Adversely Affects Chemosensitivity of Colon Cancer Cells to 5-fluorouracil.
Nutr Cancer. 2016 May 13;:1-11
Authors: Ishiguro L, Yang M, Sohn KJ, Streutker CJ, Grin A, Croxford R, Kim YI
Abstract
Folic acid (FA) fortification and widespread supplemental use have significantly increased folate status in North America. Furthermore, >50% of colorectal cancer patients use FA supplement. The increased folate status may interfere with cancer chemotherapy. We investigated the effect of FA supplementation on chemosensitivity of human colon cancer cells to 5-fluorouracil (5-FU) using a xenograft model. Mice harboring human HCT116 colon cancer xenografts were randomized to receive the control, or 4× or 12.5× supplemental levels of FA. Within each diet group, mice were randomized to receive 5-FU+leucovorin or saline and xenograft growth and characteristics were determined. The expression of genes involved in folate metabolism and cancer treatment was determined. FA supplementation and 5-FU significantly interacted to influence xenograft growth (P < 0.007). At the control level, 5-FU significantly inhibited the growth of the xenografts (P < 0.0001). However, at the 4× supplemental level, 5-FU-treated xenografts grew faster than untreated xenografts (P = 0.048) while at the 12.5× supplemental level, 5-FU exhibited no effect. Cell proliferation, degree of necrosis, and expression of the selected genes did not significantly differ by the supplemental levels of FA. Our data suggest that FA supplementation may be detrimental to 5-FU chemotherapy of colon cancer and pose public health concern.
PMID: 27175995 [PubMed - as supplied by publisher]
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Cancers, Vol. 8, Pages 49: In Hyperthermia Increased ERK and WNT Signaling Suppress Colorectal Cancer Cell Growth
Although neoplastic cells exhibit relatively higher sensitivity to hyperthermia than normal cells, hyperthermia has had variable success as an anti-cancer therapy. This variable outcome might be due to the fact that cancer cells themselves have differential degrees of sensitivity to high temperature. We hypothesized that the varying sensitivity of colorectal cancer (CRC) cells to hyperthermia depends upon the differential induction of survival pathways. Screening of such pathways revealed that Extracellular Signal-Regulated Kinase (ERK) signaling is augmented by hyperthermia, and the extent of this modulation correlates with the mutation status of V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS). Through clonal growth assays, apoptotic analyses and transcription reporter assays of CRC cells that differ only in KRAS mutation status we established that mutant KRAS cells are more sensitive to hyperthermia, as they exhibit sustained ERK signaling hyperactivation and increased Wingless/Integrated (WNT)/beta-catenin signaling. We propose that whereas increased levels of WNT and ERK signaling and a positive feedback between the two pathways is a major obstacle in anti-cancer therapy today, under hyperthermia the hyperinduction of the pathways and their positive crosstalk contribute to CRC cell death. Ascertaining the causative association between types of mutations and hyperthermia sensitivity may allow for a mutation profile-guided application of hyperthermia as an anti-cancer therapy. Since KRAS and WNT signaling mutations are prevalent in CRC, our results suggest that hyperthermia-based therapy might benefit a significant number, but not all, CRC patients.
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Recent Advances in Site Specific Conjugations of Antibody Drug Conjugates (ADCs).
Recent Advances in Site Specific Conjugations of Antibody Drug Conjugates (ADCs).
Curr Cancer Drug Targets. 2016 May 12;
Authors: Gao W, Zhang J, Xiang J, Zhang L, Wu C, Dhal PK, Chen B
Abstract
Antibody-drug conjugates (ADCs) take the advantage of antigen specificity of monoclonal antibodies to deliver highly potent cytotoxic drugs selectively to antigen-expressing tumor cells. The recent approval of Adcetris™ and Kadcyla™ as well as emerging data from numerous ongoing clinical trials underscore the role of ADCs as a new therapeutic option for cancer patients. However, conventional conjugation methods generally result in a heterogeneous mixture of ADCs, which can result in significant therapeutic liabilities and can lead to complicated manufacturing processes. The increased understanding from the clinical investigation of current ADCs and site-specific bio-conjugation technologies has enabled scientists to accelerate the discovery and development of the next generation ADCs with defined and homogeneous composition. The present manuscript reviews the recent advances and trends in the research and development of novel ADCs obtained by site-specific conjugation method.
PMID: 27174056 [PubMed - as supplied by publisher]
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G9a - an Appealing Antineoplastic Target.
G9a - an Appealing Antineoplastic Target.
Curr Cancer Drug Targets. 2016 May 12;
Authors: Chen WL, Sun HP, Li DD, Wang ZH, You QD, Guo XK
Abstract
G9a is the primary enzyme for mono- and dimethylation at Lys 9 of histone H3 (H3K9me1 and H3K9me2) and forms predominantly the heteromeric complex as a G9a-GLP (G9a-like protein) that is a functional histone lysine methltransferase in vivo. Mounting evidence suggests that G9a catalyzes methylation of histone and nonhistone proteins, which plays a crucial role in diverse biological processes and human diseases. G9a have attracted great attention of scientists as an appealing antineoplastic target. Here, we review the current knowledge on biological functions of G9a, with particular emphasis on regulating gene expression and cell processes, and involvement in human diseases. We outline a perspective on various classes of G9a inhibitors to date from both articles and patents with an emphasis on their discovery, activity and the current research status. These hold future directions and opportunities for a rapid translation of G9a inhibitors into clinical practice for a number of aggressive cancers and other human diseases.
PMID: 27174055 [PubMed - as supplied by publisher]
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Synchronous giant hepatic adenoma in siblings-A case report and brief literature review
10.1080/15384047.2016.1177682<br/>Chengsheng Zhang
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The Influence of miR-34a expression on stemness and cytotoxic susceptibility of breast cancer stem cells
10.1080/15384047.2016.1177678<br/>Hongyao Zhang
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Bcl-2 family member Mcl-1 expression is reduced under hypoxia by the E3 ligase FBW7 contributing to BNIP3 induced cell death in glioma cells
10.1080/15384047.2015.1095399<br/>Yongqiang Chen
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