Surgical Management of Liver Metastases From Colorectal Cancer [Clinical Reviews]

Surgical resection remains one of the major curative treatment options available to patients with colorectal liver metastases. Surgery and chemotherapy form the backbone of the treatment in patients with colorectal liver metastases. With more effective chemotherapy regimens being available, the optimal timing and sequencing of treatments are important. A multidisciplinary approach with the involvement of medical oncologists and surgical oncologists from the beginning is crucial. Identification of the clinical and molecular prognostic factors may help personalize the treatment approaches for these patients. This article provides an overview of the surgical management of colorectal liver metastases.

from Cancer via ola Kala on Inoreader http://ift.tt/1ZZbBxt
via IFTTT

ReCAP: Clinical Trial Assessment of Infrastructure Matrix Tool to Improve the Quality of Research Conduct in the Community [CLINICAL RESEARCH PRACTICES]

QUESTION ASKED:

Is there a tool for sites engaged in cancer clinical research to use to assess their infrastructure and improve their research conduct toward exemplary levels of performance beyond the standard of Good Clinical Practice (GCP)?

SUMMARY ANSWER:

The NCI Community Cancer Center Program (NCCCP) sites, with NCI Clinical Trial advisor input, created a "Clinical Trials Best Practice Matrix" self-assessment tool to assess research infrastructure. The tool identified nine attributes (eg, physician engagement in clinical trials, accrual activity, clinical trial portfolio diversity), each with three progressive levels (I – III) for sites to score infrastructural elements from less (I) to more (III) exemplary. For example, a level-one site might have active Phase III treatment trials in two to three disease sites and review their portfolio diversity once a year, whereas a level-three site has active Phase II and also Phase I or I/II trials across five or more disease sites and reviews their portfolio quarterly. The tool also provided a road map toward more exemplary practices.

METHODS:

From 2011 to 2013, 21 NCCCP sites self-assessed their programs with the tool annually. Sites reported significant increases in level III (more exemplary) scores across the original nine attributes combined (P < .001 [see Figure 1]). During 2013 to 2014, NCI collaborators conducted a five-step formative evaluation of the tool resulting in expansion of attributes from nine to 11 and a new name: the Clinical Trials Assessment of Infrastructure Matrix, or CT AIM, tool which is described and fully presented in the manuscript.

BIAS, CONFOUNDING FACTOR(S), DRAWBACKS:

Tool scores are self-reported which are subject to potential bias. The tool was developed by community hospital based cancer centers and has not been psychometrically validated. Use of scores for ranking between programs is not recommended at this time. The attributes and indicators in the tool may need to be adapted for other settings (eg, academic or private practice settings), and over time as research practice evolves. Not all sites can, or want to, move beyond the provision of GCP in their research programs. Adherence to GCPs meets the minimum criteria for clinical trial conduct and some of the attributes in the CT AIM can be both fiscally and administratively challenging to implement.

REAL-LIFE IMPLICATIONS:

The CT AIM tool gives community programs a tool to assess their research infrastructure as they strive to move beyond the basics of GCP to more exemplary performance. Experience within the NCCCP program suggests the CT AIM tool may be useful for improving programmatic quality, benchmarking research performance, reporting progress, and communicating program needs with institutional leaders. The tool may also be a companion to existing clinical trial education and program resources. Although used in a small group of community cancer centers, the tool may be adapted as a model in other disease disciplines.

FIG 1.

Level-three reporting for 2011, 2012, and 2013 for 21 National Cancer Institute Community Cancer Centers Program sites. Although all 21 sites completed self-assessment each year, bars do not add to 21 because the figure represents the number of sites reporting level-three score per indicator in each year. Increase in level-three scores over time across all nine attributes combined was significant at P < .001. (*) Significant P value for change over time (clinical trial communication, P = .0281; clinical trial portfolio, P = .0228).

from Cancer via ola Kala on Inoreader http://ift.tt/1J1Lvpr
via IFTTT

Colorectal Liver Metastases: A Changing Treatment Landscape [COMMENTARIES]

from Cancer via ola Kala on Inoreader http://ift.tt/1ZZbBxn
via IFTTT

ReCAP: Impact of the National Cancer Institute Community Cancer Centers Program on Clinical Trial and Related Activities at a Community Cancer Center in Rural Nebraska [HEALTH CARE DELIVERY]

QUESTION ASKED:

What is the impact of participating in the National Cancer Institute Community Cancer Centers Program (NCCCP) on the number of clinical trials available, number of patients enrolled in trials, and trial-related services provided to patients at a rural community-based cancer program?

SUMMARY ANSWER:

Significant increases in the number and percentage of patients enrolled in clinical trials, in the number of available treatment and non-treatment (eg, prevention, biospecimen, cancer control) trials, in clinical trial staffing, and in the number of tissue samples collected and/or stored were observed during the 5-year period of NCCCP. Biospecimen trials helped promote standardization of collection and storage processes in our community cancer program. Employment and utilization of a genetic counselor, smoking cessation counselor, outreach project coordinator, and two nurse navigators enabled delivery of improved cancer care continuum services to our rural patient population.

METHODS:

SFCTC clinical trial activities data from July 2002 to June 2007, the 5 years before participation in the NCCCP, and from July 2007 to June 2012, the 5 years during the program, were gathered and compared. Data capture included information on the number and percentage of patients on clinical trials, number and type of available clinical trials, percentage of underserved patients in clinical trials, clinical trial staffing, collection and storage of tissue samples, organizational infrastructure, linkage to NCI-designated cancer centers, and availability of new cancer care services. Percentages of patients in clinical trials were calculated as the ratio of the number of patients enrolled onto clinical trials over the number of analytic new patient cases of cancer through our tumor registry per year. Percentages of tissue samples collected and/or stored were similarly measured as the number of biospecimens collected over the number of analytic new patient cases of cancer per year. Statistical analyses were performed using chi-square and Wilcoxon tests.

BIAS, CONFOUNDING FACTOR(S), DRAWBACKS:

Data 5 years prior to and 5 years during NCCCP were prospectively collected. Analysis of data was performed after the completion of NCCCP.

REAL-LIFE IMPLICATIONS:

Improving access of all adult cancer patients to clinical trials in the communities where they live is crucial to provide the best cancer care. Participation in the NCCCP had a positive impact on our clinical trial and related activities, providing our rural Nebraska population with enhanced access to both clinical trials and cancer care services. Implementing programs and policies that facilitate the delivery of high-quality care in the community setting is feasible and greatly needed. The NCCCP had a positive impact by providing expanded spectrum of clinical trial types and programs to the population of patients in our cancer program service area.

Table 1.

Clinical Trial–Related Activities 5 Years Before and During NCCCP at SFCTC

Activity5 Years Before NCCCP, July 2002 to June 20075 Years of NCCCP, July 2007 to June 2012PFirst Year of NCORP, July 2014 to June 2015No. of dedicated clinical trial staffing (FTE)2 (1.2)5 (3.9).0126 (5)Total No. of accruals (range)83 (9-35)640 (51-230)90Overall participation rate in trials, % (range)3.2 (2-7)23 (9-41)< .00118Average accrual No. per clinical trial13.215.8.51.61No. of clinical trials by sponsor (range)    Cooperative46 (5-14)130 (14-29)43    Industry3 (1-2)48 (3-15)5    Investigator initiated5 (0-1)33 (2-10)8    Total54 (6-17)211 (19-54)56No. of clinical trials by type (range)    Total treatment40 (4-14)138 (14-36).01546  Average No. per year828NA    Total nontreatment15 (0-10)61 (3-33).00910  Average No. per year312NA   Supportive care010 (0-10)   Prevention03 (0-1)0   Quality of life4 (0-1)8 (1-2)0   Cancer care delivery07 (1-2)2   Biospecimen10 (2-5)33 (3-9)1Annual rate of increase in:    No. of available trials3.46.7.36NA    No. of accruals3.136.9.02NA    Percentage of accruals0.66.5.03NA

Abbreviations: FTE, full-time equivalent; NA, not applicable; NCCCP, National Cancer Institute Community Cancer Centers Program; NCORP, National Cancer Institute Community Oncology Research Program; SFCTC, Saint Francis Cancer Treatment Center.

from Cancer via ola Kala on Inoreader http://ift.tt/1J1LtOl
via IFTTT

Serum Haptoglobin as a novel molecular biomarker predicting colorectal cancer hepatic metastasis

Abstract

Early detection of liver metastasis is important for improving CRC patient survival. Our previous studies showed Haptoglobin was highly expressed in primary CRC tissues, especially in heterochronous metastatic cases. Here, we assessed the potential of serum Haptoglobin (sHP) as a biomarker for early detection of CRC liver metastasis by evaluating the sHP in 475 CRC patients and 152 healthy volunteers. In the training set (250 cases), sHP level in CRC-M1 (1773.18±690.25 ng/mL) were significantly increased as compared to in CRC-M0 (1544.37±1497.65 ng/mL) or healthy (917.76±571.59 ng/mL). And the high sHP level was correlated with poor survival. Logistic regression analysis revealed that sHP, serum carcinoembryonic antigen (sCEA) and serum carbohydrate antigen 19.9 (sCA19.9) level were the significant parameters for detecting liver metastasis. In leave-one-out-cross-validation, these three markers resulted in 89.1% sensitivity and 85.8% specificity for hepatic metastasis detection. In an independent test set (225 cases), ROC curve analysis of sHP in CRC liver metastasis showed an area under the curve (AUC) of 0.735, with a sensitivity of 87.2% and a specificity of 59.9%. Combination of sHP, sCEA and sCA19.9 improved diagnostic accuracy to 0.880, with a sensitivity of 88.5% and a specificity of 87.8%. Silencing of HP by specific shRNA significantly inhibited the Lovo and SW620 cell invasion, and suppressed xenograft tumour invasive growth. In summary, these results demonstrate that sHP is associated with poor prognosis of CRC patients and that HP promotes colorectal cancer cell invasion. sHP combining with sCA19.9 and sCEA may be used as accurate predictors of CRC liver metastasis. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/1OpO2GB
via IFTTT

Impact of deprivation on breast cancer survival among women eligible for mammographic screening in the West Midlands (UK) and New South Wales (Australia): Women diagnosed 1997-2006

Abstract

Women diagnosed with breast cancer in the UK display marked differences in survival between categories defined by socio-economic deprivation. Timeliness of diagnosis is one of the possible explanations for these patterns. Women whose cancer is screen-detected are more likely to be diagnosed at an earlier stage. We examined deprivation and screening-specific survival in order to evaluate the role of early diagnosis upon deprivation-specific survival differences in the West Midlands (England) and New South Wales (Australia). We estimated net survival for women aged 50-65 years at diagnosis and whom had been continuously eligible for screening from the age of 50. Records for 5,628 women in West Midlands (98.5% of those eligible, mean age at diagnosis 53.7 years) and 6,396 women in New South Wales (99.9% of those eligible, mean age at diagnosis 53.8 years). In New South Wales, survival was similar amongst affluent and deprived women, regardless of whether their cancer was or was not screen-detected. In the West Midlands, there were large and persistent differences in survival between affluent and deprived women. Deprivation differences were similar between the screen-detected and non-screen detected groups. These differences are unlikely to be solely explained by artefact, or by patient or tumour factors. Further investigations into the timeliness and appropriateness of the treatments received by women with breast cancer across the social spectrum in the UK are warranted. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/1RBfpUx
via IFTTT

Exploring circulating microRNA in the Neoadjuvant Treatment of Breast Cancer

Abstract

Breast cancer is the most frequently diagnosed malignancy amongst females worldwide. In recent years the management of this disease has transformed considerably, including the administration of chemotherapy in the neoadjuvant setting. Aside from increasing rates of breast conserving surgery and enabling surgery via tumour burden reduction, use of chemotherapy in the neoadjuvant setting allows monitoring of in-vivo tumour response to chemotherapeutics.

Currently, there is no effective means of identifying chemotherapeutic responders from non-responders. Whilst some patients achieve complete pathological response (pCR) to chemotherapy, a good prognostic index, a proportion of patients derive little or no benefit, being exposed to the deleterious effects of systemic treatment without any knowledge of whether they will receive benefit. The identification of predictive and prognostic biomarkers could confer multiple benefits in this setting, specifically the individualization of breast cancer management and more effective administration of chemotherapeutics. In addition, biomarkers could potentially expedite the identification of novel chemotherapeutic agents or increase their efficacy.

MicroRNAs (miRNAs) are small non-coding RNA molecules. With their tissue-specific expression, correlation with clinicopathological prognostic indices and known dysregulation in breast cancer, miRNAs have quickly become an important avenue in the search for novel breast cancer biomarkers. We provide a brief history of breast cancer chemotherapeutics and explore the emerging field of circulating (blood-borne) miRNAs as breast cancer biomarkers for the neoadjuvant treatment of breast cancer. Established molecular markers of breast cancer are outlined, while the potential role of circulating miRNAs as chemotherapeutic response predictors, prognosticators or potential therapeutic targets is discussed. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/1OpO4OH
via IFTTT

Are international differences in breast cancer survival between Australia and England present amongst both screen-detected women and non-screen-detected women? Survival estimates for women diagnosed in West Midlands and New South Wales 1997-2006

Abstract

We examined survival in screened-detected and non-screen-detected women diagnosed in the West Midlands (England) and New South Wales (Australia) in order to evaluate whether international differences in survival are related to early diagnosis, or to other factors relating to the healthcare women receive.

Women aged 50-65 years whom had been eligible for screening from 50 years were examined. Data for 5,628 women in West Midlands and 6,396 women in New South Wales were linked to screening service records (mean age at diagnosis 53.7 years). We estimated net survival and modelled the excess hazard ratio of breast cancer death by screening status.

Survival was lower for women in the West Midlands than in New South Wales (5-year net survival 90.9% [95% CI 89.9%-91.7%] compared with 93.4% [95% CI 92.6%-94.1%] respectively). The difference was greater between the two populations of non-screen-detected women (4.9%) compared to between screen-detected women, (1.8% after adjustment for lead-time and over-diagnosis). The adjusted excess hazard ratio of breast cancer death for West Midlands compared with New South Wales was greater in the non-screen detected group (EHR 2.00, 95% CI 1.70-2.31) but not significantly different to that for women whose cancer had been screen-detected (EHR 1.72, 95% CI 0.87-2.56).

In this study more than one in three breast cancer deaths in the West Midlands would have been avoided if survival had been the same as in New South Wales. The possibility that women in England receive poorer treatment is an important potential explanation which should be examined with care. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/1RBfrvr
via IFTTT

The influence of myeloid derived suppressor cells on angiogenesis and tumor growth after cancer surgery

Abstract

While myeloid-derived suppressor cells (MDSCs) have been reported to participate in the promotion of angiogenesis and tumor growth, little is known about their presence and function during peri-operative period. Here, we demonstrated that human MDSCs expressing CD11b⁺, CD33⁺ and HLA-DR^– significantly increased in lung cancer patients after thoractomy. CD11b⁺CD33⁺HLA-DR^– MDSCs isolated 24 hours after surgery from lung cancer patients were more efficient in promoting angiogenesis and tumor growth than MDSCs isolated before surgical operation in allograft tumor model. In addition, CD11b⁺CD33⁺HLA-DR^– MDSCs produced high levels of MMP-9. Using an experimental lung metastasis mouse model, we demonstrated that the numbers of metastases on lung surface and Gr-1⁺CD11b⁺ MDSCs at post-operative period were enhanced in proportion to the degree of surgical manipulation. We also examined that syngeneic bone marrow mesenchymal stem cells (BMSCs) significantly inhibited the induction and proliferation of Gr-1⁺CD11b⁺ MDSCs and further prevented lung metastasis formation in the mice undergoing laparotomy. Taken together, our results suggest that post-operatively induced MDSCs were qualified with potent pro-angiogenic and tumor promotive ability and this cell population should be considered as a target for preventing post-operative tumor metastasis. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/1RBfpUr
via IFTTT

Hepatic miR-126 is a Potential Plasma Biomarker for Detection of Hepatitis B Virus Infected Hepatocellular Carcinoma

Abstract

Controversies about the origin of circulating miRNAs have encouraged us to identify organ specific circulating miRNAs as disease biomarkers. To identify liver-specific miRNAs for hepatocellular carcinoma (HCC), global expression profiling of miRNAs in liver tissue of HBV-HCC and HBV-control with no or mild fibrosis was evaluated. A total of 40 differentially expressed miRNAs were identified in HCC. Among ten highly altered miRNAs, six miRNAs were successfully validated in tissues, whereas only two miRNAs, miR-126 and miR-142-3p showed increased expression in plasma of HBV-HCC compared to HBV-non-HCC patients. Subsequently, ROC curve analysis revealed that neither miR-126 nor miR-142-3p performed better than AFP in discriminating HCC from non-HCC while combination of each with AFP showed significantly higher efficiency rather than AFP alone (AUC: 0.922, 0.908 vs. 0.88; sensitivity: 0.84, 0.86 vs. 0.82 and specificity: 0.92, 0.94 vs. 0.86 respectively). Interestingly, triple combination of markers (miR-126+miR-142-3p+AFP) showed no additive effect on efficiency (AUC: 0.925) over the dual combination. Again, the expression of only miR-126 was noticed significantly higher in HBV-HCC patients with low-AFP [<250ng/ml] compared to either non-HCC or liver cirrhosis (AUC: 0.77, 0.64 respectively). Furthermore, no alteration in expression of mir-126 in HCV-HCC or non-viral-HCC revealed that miR-126+AFP might be specific to HBV-HCC. To understand the physiological role of these two miRNAs in hepato-carcinogenesis, target genes related to cancer pathways (APAF1, APC2, CDKN2A, IRS1, CRKL, LIFR, EGR2) were verified. Thus, combination of circulating miR-126+AFP is a promising non-invasive diagnostic biomarker for HBV-HCC and may be useful in the management of HCC patients. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/1OpO4OB
via IFTTT

Assessment of mediators of racial disparities in cervical cancer survival in the United States

Abstract

Cervical cancer (CC) morbidity and mortality have decreased in the United States, but they remain high among black women. We assessed racial disparities in CC mortality, accounting for socioeconomic status (SES). We linked data from the 1988-2007 Surveillance Epidemiology and End Results (SEER) database to the US Census. Additional SES information was obtained through linkage with Area Resource Files. We used the Kaplan-Meier method for estimating probabilities following CC diagnosis and Cox proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for CC mortality by race. The models were incrementally adjusted for marital status, registry, period, stage, and age at diagnosis, histology, treatment, household income, and poverty and unemployment rates. We stratified the analyses by disease stage and American state. A total of 44,554 women with CC were identified. Compared to white women, black women had a higher risk of dying from CC; crude and adjusted HRs were 1.41 (CI: 1.34-1.48) and 1.09 (CI: 1.03-1.15), respectively. Corresponding estimates for Hispanic women were 0.85 (CI: 0.80-0.89) and 0.75 (CI: 0.71-0.80). Black women diagnosed at late disease stages had a higher risk of CC death, whereas Hispanic women diagnosed at early and late stages had significantly lower risks. Black CC patients in California experienced poorer survival relative to white women. Conversely, longer CC survival was seen among Hispanic women in California, Georgia, and Utah. While crude estimates indicated an increased CC death risk among black women, risks diminished upon adjustment for clinical and sociodemographic characteristics. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/1RBfrf8
via IFTTT

Cancer incidence among alcoholic liver disease patients in Finland. A retrospective registry study during years 1996-2013

Abstract

Both alcohol abuse and liver cirrhosis are known risk factors for various cancers. We aimed to assess the long-term risk of malignancies among patients with severe alcoholic liver disease, i.e., alcoholic liver cirrhosis and alcoholic hepatitis. A cohort of 8796 male and 3077 female alcoholic liver disease patients from 1996-2013 was identified from the Finnish national Hospital Discharge Register. This nationwide cohort was combined with the data from the Finnish Cancer Registry for incidence of malignancies during the years 1996- 2013. The cancer cases diagnosed were compared to the number of cancers in the general population. The number of malignancies in our cohort was 1052 versus 368 expected. There was statistically significant excess of cancers of the liver, (standardized incidence ratio (SIR) 59.20; 95% CI 53.11–65.61), pancreas (SIR 37.1; 95% CI 2.72.−4.94), pharynx (SIR 9.25; 95% CI 6.05–13.56), mouth (SIR 8.31; 95% CI 4.84–13,29), esophagus (SIR 7.92; 95% CI 5.49–11.07), tongue (SIR 7,21; 95% CI 3.60–12.89), larynx (SIR 5.20; 95% CI 2.77-8.89), lung (SIR 2.77; 95% CI 2.27–3.32), stomach (SIR 2.76; 95% CI 1.79–4.07), kidney (SIR 2.69; 95% CI 1.84–3.79) and colon (SIR 2.33; 95% CI 1.70 – 3.11). There was no decreased risk of any cancer among alcoholic liver disease patients. Severe alcoholic liver disease is associated with markedly increased risk of malignancies. The risk is especially high for hepatocellular carcinoma, but also significantly increased for cancers of the upper aerodigestive tract, pancreas and kidneys, and warrants cancer surveillance in selected cases. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/1OpO2qa
via IFTTT

Lysyl oxidase like-4 monoclonal antibody demonstrates therapeutic effect against head and neck squamous cell carcinoma cells and xenografts

Abstract

A new member of the lysyl oxidase (LOX) family, lysyl oxidase-like 4 (LOXL4), is overexpressed in head and neck squamous cell carcinoma (HNSCC) compared to normal squamous epithelium. A monoclonal antibody (mAb) derived from fusion of Balb/c mouse splenocytes immunized with LOXL4 specific peptide was used to evaluate its therapeutic efficacy in 15 HNSCC cell lines associated with LOXL4 overexpression. For xenograft experiments 41 severe combined immunodeficient (SCID) mice were used to analyze LOXL4-mAb mediated tumor regression. Cell viability was analyzed using cytotoxicity-, and clonogenic-assays. Significant suppression of tumor cell growth was observed in 12 out of 15 (80%) tumor cell lines after 48h exposure to the mAb (LD50 of 15µg/ml to 45µg/ml). The effect induced by the antibody could be blocked by pre-incubation of the antibody with the peptide used for immunization of the mice and antibody generation, indicating that the effect of the antibody is specific. In mice inoculated with HNSCC cells, i.v. injections of the LOXL4-mAb resulted within 70 days in extensive tumor destruction in all treated animals whereas no tumor regression occurred in control animals. In mice pre-immunized i.v. with LOXL4-mAb and subsequently injected with HNSCC cells, tumor development was considerably delayed in contrast to non LOXL4-mAb pre-immunized animals. These results demonstrate that the LOXL4-mAb has potent antitumour activity and suggest its suitability as a therapeutic immune agent applicable to HNSCC exhibiting tumor specific up-regulation of LOXL4. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/1RBfrf6
via IFTTT

Proportion of premenopausal and postmenopausal breast cancers attributable to known risk factors: Estimates from the E3N-EPIC cohort

Abstract

Breast cancer is the most frequently diagnosed cancer among women worldwide. Breast cancer risk factors have been widely explored individually; however, little is known about their combined impact. We included 67 634 women from the French E3N prospective cohort, aged 42-72 at baseline. During a 15-year follow-up period, 497 premenopausal and 3138 postmenopausal invasive breast cancer cases were diagnosed. Population-attributable fractions (PAFs) were used to estimate cases proportions attributable to risk factors under hypothetical scenarios of lowest exposure. We examined overall premenopausal and postmenopausal invasive breast cancers and tumour subtypes (ER status and HER2 expression). Premenopausal breast cancer was not significantly attributable to non-behavioural (61.2%, -15.5% to 91.88%) nor to behavioural (39.9%, -71.0% to 93.9%) factors, contrary to postmenopausal breast cancer (41.9%, 4.5% to 68.7% and 53.5%, 12.8% to 78.7%, respectively). Individually, the highest statistically significant PAFs were obtained in premenopause for birth weight (33.6%, 5.7% to 56.6%) and age at menarche (19.8%, 5.2% to 33.6%) for non-behavioural factors and in postmenopause for history of benign breast diseases (14.9%, 11.6% to 18.0%) and age at menarche (9.7%, 3.9% to 15.5%) for non-behavioural factors and for body shape at menarche (17.1%, 9.7% to 24.3%), use of hormone replacement therapy (14.5%, 9.2% to 19.6%), dietary pattern (10.1%, 2.6% to 17.4%) and alcohol consumption (5.6%, 1.9% to 9.3%) for behavioural factors. These proportions were higher for ER+, HER2- and ER+/HER2- postmenopausal breast cancers. Our data support the hypothesis that in postmenopause, never starting unhealthy behaviours can reduce the number of diagnosed breast cancers. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/1OpO2q8
via IFTTT

A Model for Predicting Individualś Absolute Risk of Esophageal Adenocarcinoma: Moving towards Tailored Screening and Prevention

Abstract

Esophageal adenocarcinoma (EAC) is characterized by rapidly increasing incidence and poor prognosis, stressing the need for preventive and early detection strategies. We used data from a nationwide population-based case-control study, which included 189 incident cases of EAC and 820 age- and sex-matched control participants, from 1995 through 1997 in Sweden. We developed risk prediction models based on unconditional logistic regression. Candidate predictors included established and readily identifiable risk factors for EAC. The performance of model was assessed by the area under receiver operating characteristic curve (AUC) with cross-validation. The final model could explain 94% of all case patients with EAC (94% population attributable risk) and included terms for gastro-esophageal reflux symptoms or use of antireflux medication, body mass index (BMI), tobacco smoking, duration of living with a partner, previous diagnoses of esophagitis and diaphragmatic hernia, and previous surgery for esophagitis, diaphragmatic hernia, or severe reflux, or gastric or duodenal ulcer. The AUC was 0.84 (95% confidence interval [CI] 0.81-0.87) and slightly lower after cross-validation. A simpler model, based only on reflux symptoms or use of antireflux medication, BMI, and tobacco smoking could explain 91% of the case patients with EAC and had an AUC of 0.82 (95% CI 0.78-0.85). These EAC prediction models showed good discriminative accuracy, but needs to be validated in other populations. These models have the potential for future use in identifying individuals with high absolute risk of EAC in the population, who may be considered for endoscopic screening and targeted prevention. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/1RBfrf0
via IFTTT

Treatment to sustain a Th17-type phenotype to prevent skewing toward Treg and to limit premalignant lesion progression to cancer

Abstract

While immune suppression is a hallmark of head and neck squamous cell carcinoma (HSNCC), the immunological impact of premalignant oral lesions, which often precedes development of HNSCC, is unknown. The present study assessed the changes in splenic and draining lymph node CD4⁺ cell populations and their production of select cytokines that occur in mice with carcinogen-induced premalignant oral lesions and the changes that occur as lesions progress to oral cancer. These studies found skewing toward Th1 and Th17-type phenotypes in the spleen and lymph nodes of mice with premalignant oral lesions and a shift to Treg as lesions progress to cancer. Since the role of Th17 cells in the progression from premalignant lesions to cancer is not clear, studies determined the immunological and clinical effect of treating mice bearing premalignant oral lesions with a TGF-β type 1 receptor inhibitor plus IL-23 as an approach to sustain the Th17 phenotype. These studies showed that the treatment approach not only sustained the Th17 phenotype, but also increased distal spleen cell and regional lymph node cell production of other stimulatory/inflammatory mediators and slowed premalignant lesion progression to cancer. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/1OpO2q6
via IFTTT

Stress Management by Autophagy: Implications for Chemoresistance

Abstract

Development of chemoresistance, which limits the efficiency of anticancer agents, has long been a major problem in cancer therapy and urgently needs to be solved to improve clinical outcomes. Factors contributing to chemoresistance are various, but a key factor is the cell's capability for stress management. Autophagy, a favored survival strategy that organisms employ to get over many kinds of stress, is emerging as a crucial player in drug resistance. It has been shown that autophagy facilitates the resistance of tumor cells to anticancer agents, and abrogation of autophagy could be therapeutically beneficial in some cases, suggesting autophagy could be a promising target for cancer treatments. Thus, defining the roles of autophagy in chemoresistance, and the mechanisms involved, will be critical to enhance the efficiency of chemotherapy and develop novel anticancer strategy interventions. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/1RBfreS
via IFTTT

Cathepsin L inactivation leads to multimodal inhibition of prostate cancer cell dissemination in a preclinical bone metastasis model

Abstract

It is estimated that ∼90% of patients with advanced prostate cancer develop bone metastases; an occurrence that results in a substantial reduction in the quality of life and a drastic worsening of prognosis. The development of novel therapeutic strategies that impair the metastatic process and associated skeletal adversities is therefore critical to improving prostate cancer patient survival. Recognition of the importance of Cathepsin L (CTSL) to metastatic dissemination of cancer cells has led to the development of several CTSL inhibition strategies. The present investigation employed intra-cardiac injection of human PC-3ML prostate cancer cells into nude mice to examine tumor cell dissemination in a preclinical bone metastasis model. CTSL knockdown confirmed the validity of targeting this protease and subsequent intervention studies with the small molecule CTSL inhibitor KGP94 resulted in a significant reduction in metastatic tumor burden in the bone and an improvement in overall survival. CTSL inhibition by KGP94 also led to a significant impairment of tumor initiated angiogenesis. Furthermore, KGP94 treatment decreased osteoclast formation and bone resorptive function thus perturbing the reciprocal interactions between tumor cells and osteoclasts within the bone microenvironment which typically result in bone loss and aggressive growth of metastases. These functional effects were accompanied by a significant downregulation of NFκB signaling activity and expression of osteoclastogenesis related NFκB target genes. Collectively, these data indicate that the CTSL inhibitor KGP94 has the potential to alleviate metastatic disease progression and associated skeletal morbidities and hence may have utility in the treatment of advanced prostate cancer patients. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/1OpO4yc
via IFTTT

Genetic variants in ABCG1 are associated with survival of non-small cell lung cancer patients

ABSTRACT

Genetically determined cell membrane transporters and metabolic enzymes play a crucial role in the transportation of a wide variety of substrates that maintain homeostasis in biological processes. We explored associations between genetic variants in these genes and survival of non-small cell lung cancer (NSCLC) patients by re-analyzing a selected dataset from published genome-wide association studies (GWASs). In the discovery by using the GWAS dataset of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, we evaluated associations of 1,245 single nucleotide polymorphisms (SNPs) in genes of four transporter families and two metabolic enzyme families with survival of 1,185 NSCLC patients. We then performed a replication analysis in the Harvard University Lung Cancer study (LCS) with 984 NSCLC patients. Multivariate Cox proportional hazards regression and false-discovery rate (FDR) corrections were performed to evaluate the associations. We identified that 21 genotyped SNPs in eight gene regions were significantly associated with survival with FDR ≤ 0.1 in the discovery dataset. Subsequently, we confirmed six SNPs, which were putative functional, in ABCG1 of the ATP-binding cassette transporter family in the replication dataset. In the pooled analysis, two tagging (at r²>0.8 for LD with other replicated SNPs)/functional SNPs were independently associated with survival: rs225388 G>A (adjusted hazards ratio = 1.12, 95% confidence interval = 1.03-1.20, P_trend = 4.6 × 10⁻³) and rs225390 A>G (adjusted hazards ratio = 1.16, 95% confidence interval = 1.07-1.25, P_trend = 3.8 × 10⁻⁴). Our results indicated that genetic variants of ABCG1 may be predictors of survival of NSCLC patients. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/1RBfpDW
via IFTTT

Investigating the role of tumour cell derived iNOS on tumour growth and vasculature in vivo using a tetracycline regulated expression system

Abstract

Nitric oxide (NO) is a free radical signalling molecule involved in various physiological and pathological processes, including cancer. Both tumouricidal and tumour promoting effects have been attributed to NO, making its role in cancer biology controversial and unclear. To investigate the specific role of tumour-derived NO in vascular development, C6 glioma cells were genetically modified to include a doxycycline regulated gene expression system that controls the expression of an antisense RNA to inducible nitric oxide synthase (iNOS) in order to manipulate endogenous iNOS expression. Xenografts of these cells were propagated in the presence or absence of doxycycline. Susceptibility magnetic resonance imaging (MRI), initially with a carbogen (95% O₂/5% CO₂) breathing challenge and subsequently an intravascular blood pool contrast agent, was used to assess haemodynamic vasculature (ΔR₂*) and fractional blood volume (fBV), and correlated with histopathological assessment of tumour vascular density, maturation and function. Inhibition of NO production in C6 gliomas led to significant growth delay and inhibition of vessel maturation. Parametric fBV maps were used to identify vascularised regions, from which the carbogen-induced ΔR₂* was measured and found to be positively correlated with vessel maturation, quantified ex vivo using fluorescence microscopy for endothelial and perivascular cell staining. These data suggest that tumour-derived iNOS is an important mediator of tumour growth and vessel maturation, hence a promising target for anti-vascular cancer therapies. The combination of ΔR₂* response to carbogen and fBV MRI can provide a marker of tumour vessel maturation that could be applied to non-invasively monitor treatment response to iNOS inhibitors. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/1OpO4ya
via IFTTT

WCRF/AICR recommendation adherence and breast cancer incidence among postmenopausal women with and without non-modifiable risk factors

ABSTRACT

Taller height, family history of breast cancer, greater number of years of potential fertility and nulliparity are established non-modifiable risk factors for postmenopausal breast cancer. Greater adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) diet, physical activity and body weight recommendations has previously been shown to be associated with lower breast cancer risk. However, no prior studies have evaluated whether women with non-modifiable risk factors receive similar benefits from recommendation adherence compared to women without these risk factors. In the Iowa Women's Health Study prospective cohort, we investigated whether associations of WCRF/AICR recommendation adherence differed by the presence/absence of non-modifiable breast cancer risk factors. Baseline (1986) questionnaire data from 36,626 postmenopausal women were used to create adherence scores for the WCRF/AICR recommendations (maximum score=8.0). Overall and single recommendation adherence in relation to breast cancer risk (n=3,189 cases) across levels of non-modifiable risk factors were evaluated using proportional hazards regression. Mean adherence score was 5.0 points (range: 0.5–8.0). Higher adherence scores (score ≥6.0 vs. ≤3.5, HR=0.76, 95% CI=0.67–0.87), and adherence to the individual recommendations for body weight and alcohol intake were associated with a lower breast cancer incidence. While not statistically significant among women with more non-modifiable risk factors (score ≥6.0 vs. ≤3.5, HR=0.76, 95% CI=0.36–1.63), hazard ratios were comparable to women with the no non-modifiable risk factors (score ≥6.0 vs. ≤3.5, HR=0.74, 95% CI=0.49–0.93) (p-interaction=0.57). WCRF/AICR recommendation adherence is associated with lower breast cancer risk, regardless of non-modifiable risk factor status. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/1RBfqYt
via IFTTT

Gab2 facilitates epithelial-to-mesenchymal transition via the MEK/ERK/MMP signaling in colorectal cancer

Grb2-associated binder 2 (Gab2), a scaffolding adaptor protein, has recently been implicated in cancer progression. However, the role of Gab2 in the progression and metastasis of colorectal cancer (CRC) remain...

from Cancer via ola Kala on Inoreader http://ift.tt/1UMTZBf
via IFTTT

Radiation-induced miR-208a increases the proliferation and radioresistance by targeting p21 in human lung cancer cells

Lung cancer has long been the most dangerous malignant tumor among males in both well developed and poorly developed countries. Radiotherapy plays a critical role in the curative management of inoperable non-s...

from Cancer via ola Kala on Inoreader http://ift.tt/1SN6UEP
via IFTTT

JunB promotes cell invasion, migration and distant metastasis of head and neck squamous cell carcinoma

While treatment failure in cases of head and neck squamous cell carcinoma (HNSCC) frequently takes the form of locoregional recurrences and distant metastasis, our understanding of the mechanisms of metastasis...

from Cancer via ola Kala on Inoreader http://ift.tt/1UMTZ4d
via IFTTT

A New Face at the Door…

from Cancer via ola Kala on Inoreader http://ift.tt/1ngdffP
via IFTTT

Salud es Vida: a Cervical Cancer Screening Intervention for Rural Latina Immigrant Women

Abstract

This study examined the feasibility and efficacy of Salud es Vida—a promotora-led, Spanish language educational group session on cervical cancer screening (Pap tests)—self-efficacy (belief in ability to schedule and complete a Pap test), and knowledge among immigrant Hispanic/Latina women from farmworker backgrounds. These women are disproportionately burdened with cervical cancer, with mortality rates significantly higher than non-Hispanic whites. The two-arm, quasi-experimental study was conducted in four rural counties of Southeast Georgia in 2014–2015. Hispanic/Latina immigrant women aged 21–65 years and overdue for a Pap test were included as intervention (N = 38) and control (N = 52) group participants. The intervention was developed in partnership with a group of promotoras to create the toolkit of materials which includes a curriculum guide, a brochure, a flipchart, a short animated video, and in-class activities. Twelve (32 %) intervention group participants received the Pap test compared to 10 (19 %) control group participants (p = 0.178). The intervention group scored significantly higher on both cervical cancer knowledge recall and retention than the control group (p < 0.001). While there was no statistically significant difference in cervical cancer screening self-efficacy scores between the group participants, both groups scored higher at follow-up, adjusting for the baseline scores. The group intervention approach was associated with increased cervical cancer knowledge but not uptake of Pap test. More intensive interventions using patient navigation approaches or promotoras who actively follow participants or conducting one-on-one rather than group sessions may be needed to achieve improved screening outcomes with this population.

from Cancer via ola Kala on Inoreader http://ift.tt/1PV1kxz
via IFTTT

Venetoclax Adds a New Arrow Targeting Relapsed CLL to the Quiver

Publication date: 11 January 2016
Source:Cancer Cell, Volume 29, Issue 1
Author(s): Kerry A. Rogers, John C. Byrd
Inhibitors of B cell receptor signaling substantially changed the treatment of chronic lymphocytic leukemia as the first targeted agents to enter routine clinical practice. A recent paper by Roberts and colleagues describes an additional therapeutic target by reporting encouraging clinical results with venetoclax, an inhibitor of the antiapoptotic protein BCL2.

Teaser

Inhibitors of B cell receptor signaling substantially changed the treatment of chronic lymphocytic leukemia as the first targeted agents to enter routine clinical practice. A recent paper by Roberts and colleagues describes an additional therapeutic target by reporting encouraging clinical results with venetoclax, an inhibitor of the antiapoptotic protein BCL2.


from Cancer via ola Kala on Inoreader http://ift.tt/1ZiLPBY
via IFTTT

The Interaction of Myc with Miz1 Defines Medulloblastoma Subgroup Identity

Publication date: 11 January 2016
Source:Cancer Cell, Volume 29, Issue 1
Author(s): BaoHan T. Vo, Elmar Wolf, Daisuke Kawauchi, Anneli Gebhardt, Jerold E. Rehg, David Finkelstein, Susanne Walz, Brian L. Murphy, Yong Ha Youn, Young-Goo Han, Martin Eilers, Martine F. Roussel
Four distinct subgroups of cerebellar medulloblastomas (MBs) differ in their histopathology, molecular profiles, and prognosis. c-Myc (Myc) or MycN overexpression in granule neuron progenitors (GNPs) induces Group 3 (G3) or Sonic Hedgehog (SHH) MBs, respectively. Differences in Myc and MycN transcriptional profiles depend, in part, on their interaction with Miz1, which binds strongly to Myc but not MycN, to target sites on chromatin. Myc suppresses ciliogenesis and reprograms the transcriptome of SHH-dependent GNPs through Miz1-dependent gene repression to maintain stemness. Genetic disruption of the Myc/Miz1 interaction inhibited G3 MB development. Target genes of Myc/Miz1 are repressed in human G3 MBs but not in other subgroups. Therefore, the Myc/Miz1 interaction is a defining hallmark of G3 MB development.

Graphical abstract

Teaser

Myc and MycN have many similar functions but they are differentially expressed among subtypes of human medulloblastoma (MB) and they induce different experimental mouse MB subtypes. Vo et al. show that these differences are partly due to their differential binding of Miz1 and repressing gene expression.


from Cancer via ola Kala on Inoreader http://ift.tt/1J1jzBO
via IFTTT

Polycomb Repressive Complex 2 Is a Barrier to KRAS-Driven Inflammation and Epithelial-Mesenchymal Transition in Non-Small-Cell Lung Cancer

Publication date: 11 January 2016
Source:Cancer Cell, Volume 29, Issue 1
Author(s): Michela Serresi, Gaetano Gargiulo, Natalie Proost, Bjorn Siteur, Matteo Cesaroni, Martijn Koppens, Huafeng Xie, Kate D. Sutherland, Danielle Hulsman, Elisabetta Citterio, Stuart Orkin, Anton Berns, Maarten van Lohuizen
Polycomb repressive complexes (PRC) are frequently implicated in human cancer, acting either as oncogenes or tumor suppressors. Here, we show that PRC2 is a critical regulator of KRAS-driven non-small cell lung cancer progression. Modulation of PRC2 by either Ezh2 overexpression or Eed deletion enhances KRAS-driven adenomagenesis and inflammation, respectively. Eed-loss-driven inflammation leads to massive macrophage recruitment and marked decline in tissue function. Additional Trp53 inactivation activates a cell-autonomous epithelial-to-mesenchymal transition program leading to an invasive mucinous adenocarcinoma. A switch between methylated/acetylated chromatin underlies the tumor phenotypic evolution, prominently involving genes controlled by Hippo/Wnt signaling. Our observations in the mouse models were conserved in human cells. Importantly, PRC2 inactivation results in context-dependent phenotypic alterations, with implications for its therapeutic application.

Graphical abstract

Teaser

Serresi et al. identify PRC2 as a context-dependent tumor suppressor in KRAS-driven NSCLC. In p53 wild-type background, Eed loss promotes inflammation. Additional p53 inactivation leads to an invasive mucinous adenocarcinoma. A methylated/acetylated chromatin switch contributes to the phenotypic evolution.


from Cancer via ola Kala on Inoreader http://ift.tt/1J1jxtV
via IFTTT

Targeting Aberrant Epigenetic Networks Mediated by PRMT1 and KDM4C in Acute Myeloid Leukemia

Publication date: 11 January 2016
Source:Cancer Cell, Volume 29, Issue 1
Author(s): Ngai Cheung, Tsz Kan Fung, Bernd B. Zeisig, Katie Holmes, Jayant K. Rane, Kerri A. Mowen, Michael G. Finn, Boris Lenhard, Li Chong Chan, Chi Wai Eric So
Transcriptional deregulation plays a major role in acute myeloid leukemia, and therefore identification of epigenetic modifying enzymes essential for the maintenance of oncogenic transcription programs holds the key to better understanding of the biology and designing effective therapeutic strategies for the disease. Here we provide experimental evidence for the functional involvement and therapeutic potential of targeting PRMT1, an H4R3 methyltransferase, in various MLL and non-MLL leukemias. PRMT1 is necessary but not sufficient for leukemic transformation, which requires co-recruitment of KDM4C, an H3K9 demethylase, by chimeric transcription factors to mediate epigenetic reprogramming. Pharmacological inhibition of KDM4C/PRMT1 suppresses transcription and transformation ability of MLL fusions and MOZ-TIF2, revealing a tractable aberrant epigenetic circuitry mediated by KDM4C and PRMT1 in acute leukemia.

Graphical abstract

Teaser

Cheung et al. show that PRMT1 is necessary but insufficient for acute myeloid leukemia induction by chimeric transcription factors, which also recruit KDM4C for epigenetic reprogramming. Pharmacological inhibition of KDM4C/PRMT1 suppresses transcription and transformation abilities of the MOZ-TIF2 and MLL fusions.


from Cancer via ola Kala on Inoreader http://ift.tt/1ZiLPll
via IFTTT

MiR-215 Is Induced Post-transcriptionally via HIF-Drosha Complex and Mediates Glioma-Initiating Cell Adaptation to Hypoxia by Targeting KDM1B

Publication date: 11 January 2016
Source:Cancer Cell, Volume 29, Issue 1
Author(s): Jing Hu, Tao Sun, Hui Wang, Zhengxin Chen, Shuai Wang, Lifeng Yuan, Tingyu Liu, Hai-Ri Li, Pingping Wang, Yukuan Feng, Qinhong Wang, Roger E. McLendon, Allan H. Friedman, Stephen T. Keir, Darell D. Bigner, Jeff Rathmell, Xiang-dong Fu, Qi-Jing Li, Huibo Wang, Xiao-Fan Wang
The hypoxic tumor microenvironment serves as a niche for maintaining the glioma-initiating cells (GICs) that are critical for glioblastoma (GBM) occurrence and recurrence. Here, we report that hypoxia-induced miR-215 is vital for reprograming GICs to fit the hypoxic microenvironment via suppressing the expression of an epigenetic regulator KDM1B and modulating activities of multiple pathways. Interestingly, biogenesis of miR-215 and several miRNAs is accelerated post-transcriptionally by hypoxia-inducible factors (HIFs) through HIF-Drosha interaction. Moreover, miR-215 expression correlates inversely with KDM1B while correlating positively with HIF1α and GBM progression in patients. These findings reveal a direct role of HIF in regulating miRNA biogenesis and consequently activating the miR-215-KDM1B-mediated signaling required for GIC adaptation to hypoxia.

Graphical abstract

Teaser

Hu et al. reveal an HIF-miR-215-KDM1B-mediated signaling axis in adaptation of glioma-initiating cells to hypoxia, and uncover a role of HIF in post-transcriptional regulation of miRNA biogenesis through HIF-Drosha interaction. MiR-215 level in GBM correlates with HIF1α level and tumor progression in patients.


from Cancer via ola Kala on Inoreader http://ift.tt/1ZiLOxN
via IFTTT

Parsing Myc Paralogs in Oncogenesis

Publication date: 11 January 2016
Source:Cancer Cell, Volume 29, Issue 1
Author(s): Haritha Mathsyaraja, Robert N. Eisenman
Myc and its paralog MycN are thought to be functionally redundant, but Myc- and MycN-driven medulloblastomas exhibit distinct phenotypes. In this issue of Cancer Cell, Vo and colleagues (2016) show that this phenotypic difference stems from the preferential ability of Myc, relative to MycN, to bind Miz1 and repress transcription.

Teaser

Myc and its paralog MycN are thought to be functionally redundant, but Myc- and MycN-driven medulloblastomas exhibit distinct phenotypes. In this issue of Cancer Cell, Vo and colleagues (2016) show that this phenotypic difference stems from the preferential ability of Myc, relative to MycN, to bind Miz1 and repress transcription.


from Cancer via ola Kala on Inoreader http://ift.tt/1ZiLOhv
via IFTTT

GSK3 Deficiencies in Hematopoietic Stem Cells Initiate Pre-neoplastic State that Is Predictive of Clinical Outcomes of Human Acute Leukemia

Publication date: 11 January 2016
Source:Cancer Cell, Volume 29, Issue 1
Author(s): Borhane Guezguez, Mohammed Almakadi, Yannick D. Benoit, Zoya Shapovalova, Susann Rahmig, Aline Fiebig-Comyn, Fanny L. Casado, Borko Tanasijevic, Silvia Bresolin, Riccardo Masetti, Bradley W. Doble, Mickie Bhatia
Initial pathway alternations required for pathogenesis of human acute myeloid leukemia (AML) are poorly understood. Here we reveal that removal of glycogen synthase kinase-3α (GSK-3α) and GSK-3β dependency leads to aggressive AML. Although GSK-3α deletion alone has no effect, GSK-3β deletion in hematopoietic stem cells (HSCs) resulted in a pre-neoplastic state consistent with human myelodysplastic syndromes (MDSs). Transcriptome and functional studies reveal that each GSK-3β and GSK-3α uniquely contributes to AML by affecting Wnt/Akt/mTOR signaling and metabolism, respectively. The molecular signature of HSCs deleted for GSK-3β provided a prognostic tool for disease progression and survival of MDS patients. Our study reveals that GSK-3α- and GSK-3β-regulated pathways can be responsible for stepwise transition to MDS and subsequent AML, thereby providing potential therapeutic targets of disease evolution.

Graphical abstract

Teaser

Guezguez et al. show that progressive removal of glycogen synthase kinase-3 (GSK-3) signaling by Gsk3b allelic deletion results in an MDS state that, when combined with Gsk3a deletion, leads to AML. A molecular signature derived from Gsk3b-null cells has prognostic potential for MDS patients.


from Cancer via ola Kala on Inoreader http://ift.tt/1J1jz4R
via IFTTT

An Integrated Metabolic Atlas of Clear Cell Renal Cell Carcinoma

Publication date: 11 January 2016
Source:Cancer Cell, Volume 29, Issue 1
Author(s): A. Ari Hakimi, Ed Reznik, Chung-Han Lee, Chad J. Creighton, A. Rose Brannon, Augustin Luna, B. Arman Aksoy, Eric Minwei Liu, Ronglai Shen, William Lee, Yang Chen, Steve M. Stirdivant, Paul Russo, Ying-Bei Chen, Satish K. Tickoo, Victor E. Reuter, Emily H. Cheng, Chris Sander, James J. Hsieh
Dysregulated metabolism is a hallmark of cancer, manifested through alterations in metabolites. We performed metabolomic profiling on 138 matched clear cell renal cell carcinoma (ccRCC)/normal tissue pairs and found that ccRCC is characterized by broad shifts in central carbon metabolism, one-carbon metabolism, and antioxidant response. Tumor progression and metastasis were associated with metabolite increases in glutathione and cysteine/methionine metabolism pathways. We develop an analytic pipeline and visualization tool (metabolograms) to bridge the gap between TCGA transcriptomic profiling and our metabolomic data, which enables us to assemble an integrated pathway-level metabolic atlas and to demonstrate discordance between transcriptome and metabolome. Lastly, expression profiling was performed on a high-glutathione cluster, which corresponds to a poor-survival subgroup in the ccRCC TCGA cohort.

Graphical abstract

Teaser

Using metabolomic profiling, Ari Hakimi et al. show that clear cell renal cell carcinoma is characterized by broad shifts in central carbon metabolism, one-carbon metabolism, and antioxidant response. They also develop metabolograms to allow integrating the TCGA transcriptomic data with their metabolomic data.


from Cancer via ola Kala on Inoreader http://ift.tt/1J1jyOw
via IFTTT

A Biparatopic HER2-Targeting Antibody-Drug Conjugate Induces Tumor Regression in Primary Models Refractory to or Ineligible for HER2-Targeted Therapy

Publication date: 11 January 2016
Source:Cancer Cell, Volume 29, Issue 1
Author(s): John Y. Li, Samuel R. Perry, Vanessa Muniz-Medina, Xinzhong Wang, Leslie K. Wetzel, Marlon C. Rebelatto, Mary Jane Masson Hinrichs, Binyam Z. Bezabeh, Ryan L. Fleming, Nazzareno Dimasi, Hui Feng, Dorin Toader, Andy Q. Yuan, Lan Xu, Jia Lin, Changshou Gao, Herren Wu, Rakesh Dixit, Jane K. Osbourn, Steven R. Coats
Antibody-drug conjugate (ADC) which delivers cytotoxic drugs specifically into targeted cells through internalization and lysosomal trafficking has emerged as an effective cancer therapy. We show that a bivalent biparatopic antibody targeting two non-overlapping epitopes on HER2 can induce HER2 receptor clustering, which in turn promotes robust internalization, lysosomal trafficking, and degradation. When conjugated with a tubulysin-based microtubule inhibitor, the biparatopic ADC demonstrates superior anti-tumor activity over ado-trastuzumab emtansine (T-DM1) in tumor models representing various patient subpopulations, including T-DM1 eligible, T-DM1 ineligible, and T-DM1 relapsed/refractory. Our findings indicate that this biparatopic ADC has promising potential as an effective therapy for metastatic breast cancer and a broader patient population may benefit from this unique HER2-targeting ADC.

Graphical abstract

Teaser

Li et al. develop a biparatopic HER2-targeting antibody-drug conjugate that demonstrates therapeutic activity in breast cancer models representing T-DM1 eligible, resistant, and ineligible patient populations and has sufficient safety profile in non-human primates to support its translation into clinical trials.


from Cancer via ola Kala on Inoreader http://ift.tt/1J1jyOo
via IFTTT

Breast Cancer is Common in Women With Ovarian Malignant Mixed Mullerian Tumors.

Background: Ovarian malignant mixed Mullerian tumors (MMMTs) are uncommon cancers. The purpose of the study was to determine the rate of metachronous or synchronous breast cancer as well as the rate of truncating germline BRCA1 and/or BRCA2 mutations in a series of women with these uncommon tumors. Materials and Methods: Records were reviewed to identify all women with MMMTs treated by the gynecologic oncology service. The stage, grade, histology, survival, and rate of coexistent breast cancer were determined. Tumor and/or peripheral blood was tested for BRCA1 and BRCA2 truncating mutations. Results: Twenty-four patients with MMMTs were found. Tumor and paired peripheral blood was available on 20 patients and 4 more patients had only peripheral blood available. Family pedigrees were available on all 24 patients. Fifteen of 24 (62.5%) patients were found to have metachronous or synchronous breast cancers with 9 of 15 (60%) having bilateral breast cancer. No BRCA1 or BRCA2 mutations were found (somatic or germline) in this cohort. Conclusions: Although an uncommon tumor, MMMTs are often found in women with breast cancer. Despite this finding, BRCA1 or BRCA2 germline mutations are not common in this population. Precis: Ovarian MMMTs are frequently found in women with cancer but are not frequently associated with defects in BRCA1 or BRCA2. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/1mUNCl6
via IFTTT

Albumin and Neutrophil-Lymphocyte Ratio (NLR) Predict Survival in Patients With Pancreatic Adenocarcinoma Treated With SBRT.

Purpose: To determine if pretreatment nutritional status and inflammatory markers correlate with survival in patients with locally advanced pancreatic adenocarcinoma treated with stereotactic body radiotherapy (SBRT). Materials and Methods: We retrospectively reviewed 208 patients with newly diagnosed, locally advanced pancreatic adenocarcinoma treated with SBRT at our institution from 2002 to 2014. Laboratory values were collected before SBRT, including hemoglobin, platelets, albumin, red blood cell, white blood cell, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio, and tumor markers CA 19-9 and CEA. Patients were followed every 3 months with computed tomography (CT) and/or positron emission tomography-CT imaging to monitor for local recurrence and overall survival (OS). Results: Median follow-up after SBRT was 7.5 months (interquartile range, 4.6 to 12.0 mo) for all patients. Median OS for patients with NLR>5 compared with NLR5 correlate with decreased survival in patients with locally advanced pancreatic adenocarcinoma treated with SBRT, indicating the prognostic value of systemic inflammatory markers (such as NLR) and a role of nutritional supplementation to improve outcomes in these patients. Further investigation is warranted. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/1N5p4dA
via IFTTT

Primary Debulking Surgery Versus Neoadjuvant Chemotherapy in Advanced Epithelial Ovarian Cancer: A Propensity-matched Analysis.

Aims: To compare the surgical and survival outcomes of patients undergoing primary debulking surgery (PDS) versus neoadjuvant chemotherapy (NACT) plus interval debulking surgery (IDS) for advanced epithelial ovarian cancer (EOC). Materials and Methods: Consecutive patients managed for advanced EOC since 2009 were matched through a propensity score analysis, defined as the probability of a woman having PDS or NACT plus IDS. Results: The study group consisted of 100 propensity-matched women receiving PDS or NACT plus IDS. Groups resulted homogeneous in terms of baseline characteristics and pathologic findings. Patients undergoing PDS had longer operative time (P=0.032) and more blood loss (P=0.011) than the counterpart receiving NACT. No differences were found in terms of residual disease (P=0.11), as well as in terms of hospitalization, intraoperative, and postoperative complications. The mean progression-free survival was 23.0 and 27.7 months (P=0.67), whereas the overall survival (OS) was 44.5 and 43.2 months (P=0.48) for the PDS and NACT plus IDS group, respectively. Residual disease (P

from Cancer via ola Kala on Inoreader http://ift.tt/1N5p4dy
via IFTTT

The Frequency and Type of K-RAS Mutations in Mexican Patients With Colorectal Cancer: A National Study.

Background: Current metastatic colorectal cancer (mCRC) therapy uses monoclonal antibodies against the epidermal growth factor receptor. This treatment is only useful in the absence of K-RAS gene mutations; therefore the study of such mutations is part of a personalized treatment. The aim of this work is to determine the frequency and type of the most common K-RAS mutations in Mexican patients with metastatic disease by nucleotide sequencing. Patients and Methods: We studied 888 patients with mCRC from different regions of Mexico. The presence of mutations in exon 2, codons 12 and 13, of the K-RAS gene was determined by nucleotide sequencing. Results: Patients exhibited K-RAS gene mutations in 35% (310/888) of cases. Mutation frequency of codons 12 and 13 was 71% (221/310) and 29% (89/310), respectively. The most common mutation (45.7%) in codon 12 was c.35G>A (p.G12D), whereas the one in codon 13 was c.38G>A (p.G13D) (78.7%). Discussion: Given the frequency of K-RAS mutations in Mexicans, making a genetic study before deciding to treat mCRC patients with monoclonal antibodies is indispensable. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/1mUNCkV
via IFTTT

Galectin-1 is associated with poor prognosis in patients with cutaneous head and neck cancer with perineural spread

Abstract

Spread of head and neck cancer along the cranial nerves is often a lethal complication of this tumour. Current treatment options include surgical resection and/or radiotherapy, but recurrence is a frequent event suggesting that our understanding of this tumour and its microenvironment is incomplete. In this study, we have analysed the nature of the perineural tumour microenvironment by immunohistochemistry with particular focus on immune cells and molecules, which might impair anti-tumour immunity. Moderate to marked lymphocyte infiltrates were present in 58.8 % of the patient cohort including T cells, B cells and FoxP3-expressing T cells. While human leukocyte antigen (HLA) class I and more variably HLA class II were expressed on the tumour cells, this did not associate with patient survival or recurrence. In contrast, galectin-1 staining within lymphocyte areas of the tumour was significantly associated with a poorer patient outcome. Given the known role of galectin-1 in immune suppression, the data suggest that galectin inhibitors might improve the prognosis of patients with perineural spread of cancer.

from Cancer via ola Kala on Inoreader http://ift.tt/1PUDcuQ
via IFTTT

Serum elevation of B lymphocyte stimulator does not increase regulatory B cells in glioblastoma patients undergoing immunotherapy

Abstract

Regulatory B cells that secrete IL-10 (IL-10⁺ B_regs) represent a suppressive subset of the B cell compartment with prominent anti-inflammatory capacity, capable of suppressing cellular and humoral responses to cancer and vaccines. B lymphocyte stimulator (BLyS) is a key regulatory molecule in IL-10⁺ B_reg biology with tightly controlled serum levels. However, BLyS levels can be drastically altered upon chemotherapeutic intervention. We have previously shown that serum BLyS levels are elevated, and directly associated, with increased antigen-specific antibody titers in patients with glioblastoma (GBM) undergoing lymphodepletive temozolomide chemotherapy and vaccination. In this study, we examined corresponding IL-10⁺ B_reg responses within this patient population and demonstrate that the IL-10⁺ B_reg compartment remains constant before and after administration of the vaccine, despite elevated BLyS levels in circulation. IL-10⁺ B_reg frequencies were not associated with serum BLyS levels, and ex vivo stimulation with a physiologically relevant concentration of BLyS did not increase IL-10⁺ B_reg frequency. However, BLyS stimulation did increase the frequency of the overall B cell compartment and promoted B cell proliferation upon B cell receptor engagement. Therefore, using BLyS as an adjuvant with therapeutic peptide vaccination could promote humoral immunity with no increase in immunosuppressive IL-10⁺ B_regs. These results have implications for modulating humoral responses in human peptide vaccine trials in patients with GBM.

from Cancer via ola Kala on Inoreader http://ift.tt/1PUDcee
via IFTTT

8th Annual Canadian Cancer Immunotherapy Consortium (CCIC) Symposium 2015—May 20–22, Vancouver, Canada

from Cancer via ola Kala on Inoreader http://ift.tt/1mUGcy0
via IFTTT

Poly(I:C) potentiates Bacillus Calmette–Guérin immunotherapy for bladder cancer

Abstract

Non-specific immunotherapy consisting of intravesical instillation of Bacillus Calmette–Guérin (BCG) is currently the best available treatment to prevent non-muscle-invasive bladder tumor recurrence and progression. This treatment however is suboptimal, and more effective immunotherapeutic approaches are needed. Toll-like receptors (TLRs) play a major role in the activation of the immune system in response to pathogens and danger signals but also in anti-tumor responses. We previously showed that human urothelial cells express functional TLRs and respond to TLR2 and TLR3 agonists. In this study, we analyzed the potential of polyinosinic:polycytidylic acid [poly(I:C)], a TLR3 agonist, to replace or complement BCG in the treatment of non-muscle-invasive bladder cancer. We observed that poly(I:C) had an anti-proliferative, cytotoxic, and apoptotic effect in vitro on two low-grade human bladder cancer cell lines, MGH-U3 and RT4. In MGH-U3 cells, poly(I:C) induced growth arrest at the G1-S transition. Poly(I:C) also increased the immunogenicity of MGH-U3 and RT4 cells, inducing the secretion of MHC class I molecules and of pro-inflammatory cytokines. By comparison, poly(I:C) had less in vitro impact on two high-grade human bladder cancer cell lines, 5637 and T24, and on MBT-2 murine high-grade bladder cancer cells. The latter can be used as an immunocompetent model of bladder cancer. The combination poly(I:C)/BCG was much more effective in reducing MBT-2 tumor growth in mice than either treatment alone. It completely cured 29 % of mice and also induced an immunological memory response. In conclusion, our study suggests that adding poly(I:C) to BCG may enhance the therapeutic effect of BCG.

from Cancer via ola Kala on Inoreader http://ift.tt/1PUDbqO
via IFTTT

COX-2 inhibitor NS-398 suppresses doxorubicin-induced p53 accumulation through inhibition of ROS-mediated Jnk activation

Cyclooxygenase-2 (COX-2) is one of the isoforms of cyclooxygenase, a rate-limiting enzyme in the arachidonic acid cascade. COX-2 protein expression is highly induced by numerous factors and it has been reportedly overexpressed in various human malignancies. Although anti-tumorigenic effects of COX-2 inhibitors have been shown, several lines of evidence suggest that COX-2 inhibitors antagonize the cytotoxicity of chemotherapeutic agents. In this study, we investigated the effect of NS-398, a COX-2 inhibitor, on modulation of doxorubicin (DOX)-induced p53 accumulation. Non-selective and selective COX-2 inhibitors attenuated DOX-induced accumulation of wild type (WT) but not mutant p53. Nutlin-3α or MG132 abolished the suppressive effect of a COX-2 inhibitor on DOX-induced p53 increase. Moreover, the DOX-induced increase in p53 protein levels was reduced in COX-2 knockout (KO) mouse embryonic fibroblasts (MEFs) compared to those in WT or COX-1 KO MEFs. DOX-induced accumulation of p53 was attenuated by a specific inhibitor or knockdown of Jun-N-terminal kinase (Jnk). In addition, DOX-induced Jnk activation was decreased in COX-2 KO MEFs or by COX-2 inhibition, suggesting that Jnk stabilizes p53 by a mechanism that involves COX-2. Pre-treatment with a reactive oxygen species (ROS) scavenger, N-acetylcysteine, attenuated DOX-induced Jnk activation and subsequent p53 accumulation. Furthermore, the absence or inhibition of COX-2 resulted in suppression of DOX-induced increase in ROS levels. These results suggest that COX-2 activates Jnk through modulation of ROS levels, leading to accumulation of p53. Our study identifies a putative novel cross-talk between COX-2 and p53. © 2016 Wiley Periodicals, Inc.

from Cancer via ola Kala on Inoreader http://ift.tt/1RA4XMM
via IFTTT

Issue Information – UICC

from Cancer via ola Kala on Inoreader http://ift.tt/1KbjVks
via IFTTT

Issue Information – Information for Authors

from Cancer via ola Kala on Inoreader http://ift.tt/1JI1poZ
via IFTTT

Issue Information – Table of Contents

from Cancer via ola Kala on Inoreader http://ift.tt/1KbjV3T
via IFTTT

CC chemokine ligand 18(CCL18) promotes migration and invasion of lung cancer cells by binding to Nir1 through Nir1-ELMO1/DOC180 signaling pathway

Non-small cell lung cancer (NSCLC) comprises nearly 80% of lung cancers and the poor prognosis is due to its high invasiveness and metastasis. CC chemokine ligand 18 (CCL18) is predominantly secreted by M2-tumor associated macrophages (TAMs) and promotes malignant behaviors of various human cancer types. In this study, we report that the high expression of CCL18 in TAMs of NSCLC tissues and increased expression of CCL18 in TAMs is correlated with the lymph node metastasis, distant metastasis, and poor prognosis NSCLC patients. CCL18 can increase the invasive ability of NSCLC cells by binding to its receptor Nir1. In addition, CCL18 is capable of modulating cell migration and invasion by regulating the activation of RAC1 which resulted in cytoskeleton reorganization in an ELMO1 dependent manner. Furthermore, we found that CCL18 could enhance adhesion of NSCLC cells via activating ELMO1-integrin β1 signaling. Thus, CCL18 and its downstream molecules may be used as targets to develop novel NSCLC therapy. © 2016 Wiley Periodicals, Inc.

from Cancer via ola Kala on Inoreader http://ift.tt/1PU9jL5
via IFTTT

Targeting c-MET by LY2801653 for treatment of cholangiocarcinoma

Palliative treatment options for human cholangiocarcinoma (CCC) are quite limited and new therapeutic strategies are of utmost need. c-MET has been shown to be deregulated in many cancers, but the role of c-MET in the carcinogenesis of CCC remains unclear. The main purpose of this study is to evaluate the expression and also to investigate the role of c-MET and its effective inhibition for the treatment of CCC. In this study we investigated the effects of LY2801653, a small-molecule inhibitor with potent activity against MET kinase, in human CCC cell lines and in vivo using a xenograft mouse model. We have investigated the role of c-MET and its inhibitory effects on migration, invasion, colony formation, MET downstream targets, and CCC tumor growth. We also analyzed the role of apoptosis and senescence as well as the influence of hypoxia in this context. c-MET and p-MET were expressed in 72% and 12.5% of human CCC tissues and in TFK-1, SZ-1 cell lines. MET inhibition was achieved by blocking phosphorylation of MET with LY2801653 and subsequent down regulation of c-MET downstream targets. Treatment showed in a xenograft model potent anti-tumor activity. LY2801653 is an effective inhibitor and suppress the proliferation of CCC cells as well as the growth of xenograft tumors. Therefore, inhibition of c-MET could be a possible alternative approach for the treatment of human CCC. © 2016 Wiley Periodicals, Inc.

from Cancer via ola Kala on Inoreader http://ift.tt/1SfO1ek
via IFTTT

Integrated analysis of DNA methylation and mutations in esophageal squamous cell carcinoma

The recent development of next-generation sequencing technology for extensive mutation analysis, and beadarray technology for genome-wide DNA methylation analysis has made it possible to obtain integrated pictures of genetic and epigenetic alterations, using the same cancer samples. In this study, we aimed to characterize such a picture in esophageal squamous cell carcinomas (ESCCs). Base substitutions of 55 cancer-related genes and copy number alterations (CNAs) of 28 cancer-related genes were analyzed by targeted sequencing. Forty-four of 57 ESCCs (77%) had 64 non-synonymous somatic mutations, and 24 ESCCs (42%) had 35 CNAs. A genome-wide DNA methylation analysis using an Infinium HumanMethylation450 BeadChip array showed that the CpG island methylator phenotype was unlikely to be present in ESCCs, a different situation from gastric and colon cancers. Regarding individual pathways affected in ESCCs, the WNT pathway was activated potentially by aberrant methylation of its negative regulators, such as SFRP1, SFRP2, SFRP4, SFRP5, SOX17, and WIF1 (33%). The p53 pathway was inactivated by TP53 mutations (70%), and potentially by aberrant methylation of its downstream genes. The cell cycle was deregulated by mutations of CDKN2A (9%), deletions of CDKN2A and RB1 (32%), and by aberrant methylation of CDKN2A and CHFR (9%). In conclusion, ESCCs had unique methylation profiles different from gastric and colon cancers. The genes involved in the WNT pathway were affected mainly by epigenetic alterations, and those involved in the p53 pathway and cell cycle regulation were affected mainly by genetic alterations. © 2016 Wiley Periodicals, Inc.

from Cancer via ola Kala on Inoreader http://ift.tt/1PU9je0
via IFTTT