Prevalence of human papillomavirus in saliva of women with HPV genital lesions

Abstract

Background

The human papilloma viruses (HPVs) are DNA viruses associated with benign and malignant lesions of skin and mucous membranes. The HPVs has been implicated as the cause of virtually all cervical cancers worldwide but studies showed that these viruses can cause numerous cancers in several tissues including Oral Squamous Cell Carcinoma (OSCC). At least 90 % of HPV-positive OSCCs are associated with high-risk (or oncogenic) HPV-16 and oral infection confers an approximate 50-fold increase in risk for HPV-positive OSCC. HPV-positive OSCCs are associated with sexual behaviors in contrast to HPV-negative OSCCs that are associated with chronic tobacco and alcohol use. The aim of this study was to estimate the prevalence of HPV-DNA in saliva samples collected from women in which it has been previously established the HPV infection of the cervix with relative genotyping and, then, to study the possible correlation.

Methods

Saliva samples were collected from 100 women with HPV cervical lesions, aged between 22 and 52 years old, and 25 healthy women with normal cytology (control group), aged between 20 and 49 years old. PCR assay was used to detect HPV DNA.

Results

The prevalence of oral HPV infection in saliva samples was 24 % in women with HPV cervical lesions while in the control group was 8 %. It has been demonstrated a strong association between high grade squamous intraepithelial lesion and oral infection due to HPV16 and 18, that are the most frequently detected HPV genotypes.

Conclusion

This study shows that patients with genital HPV infection are at risk for oral infection and, consequently, for the development of OSCC.

from Cancer via ola Kala on Inoreader http://ift.tt/2bkhy3U
via IFTTT

Does Specialty Bias Trump Evidence in the Management of High-risk Prostate Cancer?.

Objective: The objective was to query how specialty influences treatment recommendations for high-risk prostate cancer in 3 clinical settings: upfront management, postoperative management, and management of biochemical recurrences (BCRs) after radiotherapy (RT). We hypothesized that specialty bias would manifest in all settings, trumping available evidence. Methods: A survey of practicing urologists and radiation oncologists was distributed through electronic mail. Questions pertained to upfront management, postoperative treatment, and local salvage for postradiation BCRs. The associations between 26 selected categorical responses and specialty were assessed using multivariate logistic regression. Training level/expertise, practice setting, percentage of consultation caseload consisting of prostate cancer, and nationality were set as effect modifiers. Results: One thousand two hundred fifty-three physicians (846 radiation oncologists and 407 urologists) completed the survey. Radiation oncologists were more likely to recommend adjuvant RT and consider it to be underutilized, and more likely to recommend salvage RT at lower prostate-specific antigen thresholds (P

from Cancer via ola Kala on Inoreader http://ift.tt/2bEpuh3
via IFTTT

Renal cell carcinoma with inferior vena cava involvement: Prognostic effect of tumor thrombus consistency on cancer specific survival

Background

Renal cell carcinoma forming a venous tumor thrombus (VTT) in the inferior vena cava (IVC) has a poor prognosis. Recent investigations have been focused on prognostic markers of survival. Thrombus consistency (TC) has been proposed to be of significant value but yet there are conflicting data. The aim of this study is to test the effect of IVC VTT consistency on cancer specific survival (CSS) in a multi-institutional cohort.

Methods

The records of 413 patients collected by the International Renal Cell Carcinoma–Venous Thrombus Consortium were retrospectively analyzed. All patients underwent radical nephrectomy and tumor thrombectomy. Kaplan–Meier estimate and Cox regression analyses investigated the impact of TC on CSS in addition to established clinicopathological predictors.

Results

VTT was solid in 225 patients and friable in 188 patients. Median CSS was 50 months in solid and 45 months in friable VTT. TC showed no significant association with metastatic spread, pT stage, perinephric fat invasion, and higher Fuhrman grade. Survival analysis and Cox regression rejected TC as prognostic marker for CSS.

Conclusions

In the largest cohort published so far, TC seems not to be independently associated with survival in RCC patients and should therefore not be included in risk stratification models. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

from Cancer via ola Kala on Inoreader http://ift.tt/2bC4xWZ
via IFTTT

Early signet ring cell carcinoma of the stomach is related to favorable prognosis and low incidence of lymph node metastasis

Background

The aim of this study was to evaluate the clinical characteristics of early signet ring cell carcinoma of the stomach (SRC) and to investigate the optimal treatment strategy for early SRC.

Methods

A total of 746 patients with pT1 gastric cancer (GC), who had undergone surgical resection between 1997 and 2012 were analyzed. Of these, 190 patients with SRC were enrolled in this study.

Results

(i) The patients with SRC showed a significantly longer overall survival (P = 0.012) and disease free survival (P = 0.004) than patients with the other histological types. Multivariate analysis identified SRC as an independent factor predicting favorable prognosis in pT1 GC (HR = 0.38; 95% CI: 0.11–0.96; P = 0.041). Specifically, in undifferentiated pT1 GC, SRC was significantly less associated with lymph node metastasis (LNM) (OR = 0.39; 95% CI: 0.15–0.96; P = 0.042). (ii) From the viewpoint of a histological mixed-type, pure-SRC with pT1a was not associated with LNM regardless of tumor size (0.0%, 0/110), whereas mixed-SRC was an independent risk factor for LNM (OR = 7.19; 95% CI: 1.51–43.9; P = 0.012).

Conclusions

Patients with early SRC have a favorable prognosis with a low incidence of LNM. However, care should be taken with mixed-SRC, which consists of SRC and other histological types. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

from Cancer via ola Kala on Inoreader http://ift.tt/2bTSZvO
via IFTTT

Highlights from the Literature

from Cancer via ola Kala on Inoreader http://ift.tt/2bEBB1Y
via IFTTT

Phase I trial of p28 (NSC745104), a non-HDM2-mediated peptide inhibitor of p53 ubiquitination in pediatric patients with recurrent or progressive central nervous system tumors: A Pediatric Brain Tumor Consortium Study

Background

p53 is a promising target in human cancer. p28 is a cell-penetrating peptide that preferentially enters cancer cells and binds to both wild-type and mutant p53 protein, inhibiting COP1-mediated ubiquitination and proteasomal degradation. This results in increased levels of p53, which induces cell cycle arrest at G₂/M. We conducted a phase I study to determine the maximum-tolerated dose (MTD) and describe the dose-limiting toxicities (DLTs) and pharmacokinetics (PKs) of p28 in children.

Methods

Children aged 3–21 years with recurrent or progressive central nervous system tumors were eligible. Intravenous p28 was administered 3 times weekly for 4 consecutive weeks of a 6-week cycle at 4.16 mg/kg/dose (the adult recommended phase II dose) using a rolling-6 study design. Expression status of p53 was characterized by immunohistochemistry, and serum PK parameters were established on the second dose.

Results

Of the 18 eligible patients enrolled in the study, 12 completed the DLT monitoring period and were evaluable for toxicity. p28 was well-tolerated; 7 participants received ≥2 courses, and the most common adverse event attributed to the drug was transient grade 1 infusion-related reaction. PK analysis revealed a profile similar to adults; however, an increased area under the curve was observed in pediatric patients. High p53 expression in tumor cell nuclei was observed in 6 of 12 available tissue samples. There were no objective responses; 2 participants remained stable on the study for >4 cycles.

Conclusions

This phase I study demonstrated that p28 is well-tolerated in children with recurrent CNS malignancies at the adult recommended phase II dose.

from Cancer via ola Kala on Inoreader http://ift.tt/2bDvOFA
via IFTTT

Response Assessment in Neuro-Oncology working group and European Association for Neuro-Oncology recommendations for the clinical use of PET imaging in gliomas

This guideline provides recommendations for the use of PET imaging in gliomas. The review examines established clinical benefit in glioma patients of PET using glucose (¹⁸F-FDG) and amino acid tracers (¹¹C-MET, ¹⁸F-FET, and ¹⁸F-FDOPA). An increasing number of studies have been published on PET imaging in the setting of diagnosis, biopsy, and resection as well radiotherapy planning, treatment monitoring, and response assessment. Recommendations are based on evidence generated from studies which validated PET findings by histology or clinical course. This guideline emphasizes the clinical value of PET imaging with superiority of amino acid PET over glucose PET and provides a framework for the use of PET to assist in the management of patients with gliomas.

from Cancer via ola Kala on Inoreader http://ift.tt/2bECpUz
via IFTTT

Announcements

from Cancer via ola Kala on Inoreader http://ift.tt/2bDvIxO
via IFTTT

Creation of an NCI comparative brain tumor consortium: informing the translation of new knowledge from canine to human brain tumor patients

On September 14–15, 2015, a meeting of clinicians and investigators in the fields of veterinary and human neuro-oncology, clinical trials, neuropathology, and drug development was convened at the National Institutes of Health campus in Bethesda, Maryland. This meeting served as the inaugural event launching a new consortium focused on improving the knowledge, development of, and access to naturally occurring canine brain cancer, specifically glioma, as a model for human disease. Within the meeting, a SWOT (strengths, weaknesses, opportunities, and threats) assessment was undertaken to critically evaluate the role that naturally occurring canine brain tumors could have in advancing this aspect of comparative oncology aimed at improving outcomes for dogs and human beings. A summary of this meeting and subsequent discussion are provided to inform the scientific and clinical community of the potential for this initiative. Canine and human comparisons represent an unprecedented opportunity to complement conventional brain tumor research paradigms, addressing a devastating disease for which innovative diagnostic and treatment strategies are clearly needed.

from Cancer via ola Kala on Inoreader http://ift.tt/2bED6x7
via IFTTT

A new patient-derived orthotopic malignant meningioma model treated with oncolytic herpes simplex virus

Background

Higher-grade meningiomas (HGMs; World Health Organization grades II and III) pose a clinical problem due to high recurrence rates and the absence of effective therapy. Preclinical development of novel therapeutics requires a disease model that recapitulates the genotype and phenotype of patient HGM. Oncolytic herpes simplex virus (oHSV) has shown efficacy and safety in cancers in preclinical and clinical studies, but its utility for HGM has not been well characterized.

Methods

Tumorsphere cultures and serial orthotopic xenografting in immunodeficient mice were used to establish a patient-derived HGM model. The model was pathologically and molecularly characterized by immunohistochemistry, western blot, and genomic DNA sequencing and compared with the patient tumor. Anti-HGM effects of oHSV G47 were assessed using cell viability and virus replication assays in vitro and animal survival analysis following intralesional injections of G47.

Results

We established a serially transplantable orthotopic malignant meningioma model, MN3, which was lethal within 3 months after tumorsphere implantation. MN3 xenografts exhibited the pathological hallmarks of malignant meningioma such as high Ki67 and vimentin expression. Both the patient tumor and xenografts were negative for neurofibromin 2 (merlin) and had the identical NF2 mutation. Oncolytic HSV G47 efficiently spread and killed MN3 cells, as well as other patient-derived HGM lines in vitro. Treatment with G47 significantly extended the survival of mice bearing subdural MN3 tumors.

Conclusions

We established a new patient-derived meningioma model that will enable the study of targeted therapeutic approaches for HGM. Based on these studies, it is reasonable to consider a clinical trial of G47 for HGM.

from Cancer via ola Kala on Inoreader http://ift.tt/2bDvKWm
via IFTTT

Glycolysis and the pentose phosphate pathway are differentially associated with the dichotomous regulation of glioblastoma cell migration versus proliferation

Background

The dichotomy between glioblastoma cell migration and proliferation is regulated by various parameters including oxygen tension. In glioblastoma stem-like cells, hypoxia induces downregulation of pentose phosphate pathway (PPP) enzymes and a flux shift towards glycolysis. We investigated whether the 2 parallel glucose metabolic pathways are intrinsically linked with cell function and whether these pathways are mechanistically involved in regulating functional programs.

Methods

Enzyme expression, migration, and proliferation under hypoxia were studied in multiple cell types. Rapidly and slowly dividing or migrating glioblastoma cells were separated, and enzyme profiles were compared. Glucose-6-phosphate dehydrogenase (G6PD) and Aldolase C (ALDOC), the most strongly inversely regulated PPP and glycolysis enzymes, were knocked down by short hairpin RNA.

Results

Hypoxia caused downregulation of PPP enzymes and upregulation of glycolysis enzymes in a broad spectrum of cancer and nonneoplastic cells and consistently stimulated migration while reducing proliferation. PPP enzyme expression was increased in rapidly dividing glioblastoma cells, whereas glycolysis enzymes were decreased. Conversely, glycolysis enzymes were elevated in migrating cells, whereas PPP enzymes were diminished. Knockdown of G6PD reduced glioblastoma cell proliferation, whereas ALDOC knockdown decreased migration. Enzyme inhibitors had similar effects. G6PD knockdown in a highly proliferative but noninvasive glioblastoma cell line resulted in prolonged survival of mice with intracerebral xenografts, whereas ALDOC knockdown shortened survival. In a highly invasive glioblastoma xenograft model, tumor burden was unchanged by either knockdown.

Conclusions

Cell function and metabolic state are coupled independently of hypoxia, and glucose metabolic pathways are causatively involved in regulating "go or grow" cellular programs.

from Cancer via ola Kala on Inoreader http://ift.tt/2bEChES
via IFTTT

Primary CNS lymphoma at first relapse/progression: characteristics, management, and outcome of 256 patients from the French LOC network

Background

Treatment of relapsed/refractory (R/R) primary CNS lymphoma (PCNSL) is poorly defined, because randomized trials and large studies are lacking. The aim of this study was to analyze the characteristics, management, and outcome of R/R PCNSL patients after first-line therapy in a nationwide cohort.

Methods

We analyzed R/R PCNSL patients following first-line treatment who had been prospectively registered in the database of the French network for oculocerebral lymphoma (LOC) between 2011 and 2014.

Results

Among 563 PCNSL patients treated with first-line therapy, we identified 256 with relapsed (n = 93, 16.5%) or refractory (n = 163, 29.0%) disease. Patients who were asymptomatic at relapse/progression (25.5%), mostly diagnosed on routine follow-up neuroimaging, tended to have a better outcome. Patients who received salvage therapy followed by consolidation (mostly intensive chemotherapy plus autologous hematopoietic stem cell transplantation [ICT + AHSCT]) experienced prolonged survival compared with those who did not receive salvage or consolidation therapy. Independent prognostic factors at first relapse/progression were: KPS ≥ 70 vs KPS < 70), sensitivity to first-line therapy (relapsed vs refractory disease), duration of first remission (progression-free survival [PFS] ≥1 y vs <1 y), and management at relapse/progression (palliative care vs salvage therapy). Patients who relapsed early after first-line therapy (ie, PFS < 1 y) had a poor outcome, comparable to that of refractory patients. Conversely, patients experiencing late relapses (PFS ≥ 1 y) and/or undergoing consolidation with ICT + AHSCT experienced prolonged survival.

Conclusions

About a third of PCNSL patients are primary refractory to first line treatment. We identified several independent prognostic factors that can guide the management of R/R PCNSL patients.

from Cancer via ola Kala on Inoreader http://ift.tt/2bDwhaW
via IFTTT

Novel MET/TIE2/VEGFR2 inhibitor altiratinib inhibits tumor growth and invasiveness in bevacizumab-resistant glioblastoma mouse models

Background

Glioblastoma highly expresses the proto-oncogene MET in the setting of resistance to bevacizumab. MET engagement by hepatocyte growth factor (HGF) results in receptor dimerization and autophosphorylation mediating tumor growth, invasion, and metastasis. Evasive revascularization and the recruitment of TIE2-expressing macrophages (TEMs) are also triggered by anti-VEGF therapy.

Methods

We investigated the activity of altiratinib (a novel balanced inhibitor of MET/TIE2/VEGFR2) against human glioblastoma stem cell lines in vitro and in vivo using xenograft mouse models. The biological activity of altiratinib was assessed in vitro by testing the expression of HGF-stimulated MET phosphorylation as well as cell viability after altiratinib treatment. Tumor volume, stem cell and mesenchymal marker levels, microvessel density, and TIE2-expressing monocyte infiltration were evaluated in vivo following treatment with a control, bevacizumab alone, bevacizumab combined with altiratinib, or altiratinib alone.

Results

In vitro, HGF-stimulated MET phosphorylation was completely suppressed by altiratinib in GSC17 and GSC267, and altiratinib markedly inhibited cell viability in several glioblastoma stem cell lines. More importantly, in multiple xenograft mouse models, altiratinib combined with bevacizumab dramatically reduced tumor volume, invasiveness, mesenchymal marker expression, microvessel density, and TIE2-expressing monocyte infiltration compared with bevacizumab alone. Furthermore, in the GSC17 xenograft model, altiratinib combined with bevacizumab significantly prolonged survival compared with bevacizumab alone.

Conclusions

Together, these data suggest that altiratinib may suppress tumor growth, invasiveness, angiogenesis, and myeloid cell infiltration in glioblastoma. Thus, altiratinib administered alone or in combination with bevacizumab may overcome resistance to bevacizumab and prolong survival in patients with glioblastoma.

from Cancer via ola Kala on Inoreader http://ift.tt/2bECGXG
via IFTTT

Upfront bevacizumab may extend survival for glioblastoma patients who do not receive second-line therapy: an exploratory analysis of AVAglio

Background

In this post-hoc, exploratory analysis, we examined outcomes for patients enrolled in the AVAglio trial of front-line bevacizumab or placebo plus radiotherapy/temozolomide who received only a single line of therapy.

Methods

Patients with newly diagnosed glioblastoma received protocol-defined treatment until progressive disease (PD). Co-primary endpoints were investigator-assessed progression-free survival (PFS) and overall survival (OS). After confirmed PD, patients were treated at the investigators' discretion. PFS/OS were assessed in patients with a PFS event who did not receive post-PD therapy (Group 1) and patients with a PFS event who received post-PD therapy plus patients who did not have a PFS event at the final data cutoff (Group 2). Kaplan–Meier methodology was used. A multivariate Cox proportional hazards model for known prognostic variables was generated.

Results

Baseline characteristics were balanced. In patients with a PFS event who did not receive post-PD therapy (Group 1; n = 225 [24.4% of the intent-to-treat population]), the addition of bevacizumab to radiotherapy/temozolomide resulted in a 3.6-month extension in both median PFS (hazard ratio [HR]: 0.62, P = .0016) and median OS (HR: 0.67, P = .0102). Multivariate analyses supported this OS benefit (HR: 0.66). In the remaining patients (Group 2; n = 696), a 5.2-month PFS extension was observed in bevacizumab-treated patients (HR: 0.61, P < .0001); OS was comparable between the treatment arms (HR: 0.88, P = .1502). No significant differences in safety were observed between the 2 groups.

Conclusion

This exploratory analysis suggests that the addition of bevacizumab to standard glioblastoma treatment prolongs PFS and OS for patients with PD who receive only one line of therapy.

from Cancer via ola Kala on Inoreader http://ift.tt/2bDvwOR
via IFTTT

Corrigendum

from Cancer via ola Kala on Inoreader http://ift.tt/2bECtDO
via IFTTT

Assessing Quality of Care for the Myelodysplastic Syndromes

Abstract

Measuring the quality of care for patients with chronic cancers is difficult, especially for heterogeneous malignancies such as the myelodysplastic syndromes (MDS). Recent work suggests that improvements may be needed in the quality of diagnostic, treatment, and end-of-life care for patients with these syndromes. Moreover, rigorous assessment of factors that are necessary to deliver high-quality care such as preferred method of decision-making and pre-treatment quality of life are often overlooked. Finally, a key component of quality care is that it is received equitably across different patient populations, yet several recent studies suggest that there are financial, educational, race-ethnic, and age-related barriers to equitable MDS care.

from Cancer via ola Kala on Inoreader http://ift.tt/2bSE7xR
via IFTTT

Adding checkpoint inhibitors to tyrosine kinase inhibitors targeting EGFR/ALK in non-small cell lung cancer: a new therapeutic strategy

Summary

After the massive approval of checkpoint inhibitors in the treatment of numerous malignancies and settings, checkpoint inhibitors-based combination therapies are emerging as a new therapeutic modality. Nivolumab and pembrolizumab (anti-PD1 agents) were recently approved as second-line treatment in NSCLC after progression on platinum-doublets. In parallel, targeting EGFR/ALK in NSCLC using tyrosine kinase inhibitors (TKI) demonstrated remarkable outcomes and was approved as standard treatment, in patients with EGFR mutation or ALK rearrangement. Combining TKI targeting EGFR/ALK with checkpoint inhibitors seems a promising therapeutic option and is being evaluated in different trials. We aimed in this paper to elucidate the rationale behind this combination, to report the premilinary results of ongoing trials evaluating this association and finally, to discuss briefly the possible future indication of this treatment modality.

from Cancer via ola Kala on Inoreader http://ift.tt/2bJteji
via IFTTT

Risk of cancer in Asian Americans: a Kaiser Permanente cohort study

Abstract

Purpose

To supplement published cohort data about incident cancer in Asian Americans (Asians) including risk of specific Asian ethnic groups.

Methods

A cohort study in 124,193 persons (13,344 Asians) with baseline examination data in 1978–1985 used Cox proportional hazards models with seven covariates to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs).

Results

Through 2012 cancer was diagnosed in 18,687 persons including 1,522 Asians. Compared to Whites, the HR (CIs) for any cancer in Asians was 0.8 (0.7–0.9, p < 0.001). Lower Asian risk was stronger for men (HR = 0.7, p < 0.001) than for women (HR = 0.9, p = 0.003). Lower Asian vs. White risks with p < 0.05 were found for cancers of the upper airway digestive area, hematologic malignancies, melanoma, and cancers of the prostate, bladder, and brain. Melanoma contributed substantially to lower Asian risk, especially in women. HRs for specific Asian groups versus Whites follow: Chinese = 0.9 (p < 0.001), Japanese = 0.9 (p = 0.01), Filipinos = 0.8 (p < 0.001), South Asians = 0.5 (p < 0.001), and Other Asians = 0.7 (p = 0.006). Both South Asian men and women had lower risk than Whites, and South Asians had lower risk than any other racial/ethnic group.

Conclusions

Asians had lower cancer risk than Whites, due to lower risk of several cancer types. Each Asian ethnic group had lower risk than Whites with South Asians at the lowest risk.

from Cancer via ola Kala on Inoreader http://ift.tt/2bmotJG
via IFTTT

Equity, barriers and cancer disparities: study of the Spanish Society of Medical Oncology on the access to oncologic drugs in the Spanish Regions

Abstract

Purpose

The Spanish Society of Medical Oncology (SEOM) has conducted a study on the access to oncologic drugs across the 17 Spanish Regions with the aim of identifying potential heterogeneities and making proposals for eliminating the barriers identified at the different levels.

Methods

An Expert Panel made up of medical oncologists designed a survey on certain indications approved for 11 drugs in the approach of breast cancer, melanoma, lung cancer, prostate cancer and support treatment. This survey was sent to 144 National Health System (NHS) hospitals.

Results

77 hospitals answered the survey. The information modules analysed were: scope of the Commission that establishes binding decisions related to drug access; conditions, stages and periods of drug application, approval and administration processes; barriers to accessing drugs.

Conclusions

The study shows variability in drug access. The SEOM makes proposals addressed to reducing the differences identified and homogenizing drug access conditions.

from Cancer via ola Kala on Inoreader http://ift.tt/2blYrWV
via IFTTT

Equity, barriers and cancer disparities: study of the Spanish Society of Medical Oncology on the access to oncologic drugs in the Spanish Regions

Abstract

Purpose

The Spanish Society of Medical Oncology (SEOM) has conducted a study on the access to oncologic drugs across the 17 Spanish Regions with the aim of identifying potential heterogeneities and making proposals for eliminating the barriers identified at the different levels.

Methods

An Expert Panel made up of medical oncologists designed a survey on certain indications approved for 11 drugs in the approach of breast cancer, melanoma, lung cancer, prostate cancer and support treatment. This survey was sent to 144 National Health System (NHS) hospitals.

Results

77 hospitals answered the survey. The information modules analysed were: scope of the Commission that establishes binding decisions related to drug access; conditions, stages and periods of drug application, approval and administration processes; barriers to accessing drugs.

Conclusions

The study shows variability in drug access. The SEOM makes proposals addressed to reducing the differences identified and homogenizing drug access conditions.

from Cancer via ola Kala on Inoreader http://ift.tt/2blYrWV
via IFTTT

The metronomic therapy with prednisone, etoposide, and cyclophosphamide reduces the serum levels of VEGF and circulating endothelial cells and improves response rates and progression-free survival in patients with relapsed or refractory non-Hodgkin’s lymphoma

Abstract

Purpose

There is an urgent need for a better strategy in the management of relapsed or refractory non-Hodgkin's lymphoma (NHL). The present study was designed to evaluate the efficacy and safety of the regimen using metronomic prednisone, etoposide, and cyclophosphamide in the treatment of patients with relapsed or refractory NHL, in comparison with conventional salvage chemotherapy.

Methods

Eligible patients were randomized to the test group (n = 23) receiving metronomic prednisone, etoposide, and cyclophosphamide or the control group (n = 21) receiving conventional salvage chemotherapy. The serum levels of circulating endothelial cells (CECs) and vascular endothelial growth factor (VEGF) were measured before and after two cycles of treatment; overall response rate (ORR) and disease control rate (DCR) were evaluated at cycles 2, 4, 6, and 12 months after treatment.

Results

After two cycles of treatment, the ORRs of the test and control groups were statistically similar, while the DCR of the test group (87.0 %) was significantly higher than that of the control group (57.1 %). At 12 months after treatment, the ORR and DCR of the test group (47.8 and 69.6 %, respectively) were significantly higher than that of the control group (19.0 and 33.3 %, respectively). The serum CECs and VEGF levels in the test group after treatment were significantly lower than that before treatment or that of the control group. In the patients with ORR and DCR in the test group, the serum CECs and VEGF levels remained relatively low at cycles 2, 4, and 6 and at 12 months after treatment. There was a progression-free survival (PFS) benefit of 6.5 months in the test group, compared with the control group.

Conclusion

Metronomic chemotherapy with prednisone, etoposide, and cyclophosphamide resulted in higher ORR and DCR, fewer adverse effects, and longer PFS in patients with relapsed or refractory NHL, with significant reduction in serum CECs and VEGF levels.

from Cancer via ola Kala on Inoreader http://ift.tt/2bSkXti
via IFTTT

Erratum to: Comparative Analysis of Length of Stay and Inpatient Costs for Orthopedic Surgery Patients Treated with IV Acetaminophen and IV Opioids vs. IV Opioids Alone for Post-Operative Pain

from Cancer via ola Kala on Inoreader http://ift.tt/2blXVbv
via IFTTT

Multidisciplinary Consideration of Potential Pathophysiologic Mechanisms of Paradoxical Erythema with Topical Brimonidine Therapy

Abstract

Rosacea is a chronic inflammatory disease with transient and non-transient redness as key characteristics. Brimonidine is a selective α2-adrenergic receptor (AR) agonist approved for persistent facial erythema of rosacea based on significant efficacy and good safety data. The majority of patients treated with brimonidine report a benefit; however, there have been sporadic reports of worsening erythema after the initial response. A group of dermatologists, receptor physiology, and neuroimmunology scientists met to explore potential mechanisms contributing to side effects as well as differences in efficacy. We propose the following could contribute to erythema after application: (1) local inflammation and perivascular inflammatory cells with abnormally functioning ARs may lead to vasodilatation; (2) abnormal saturation and cells expressing different AR subtypes with varying ligand affinity; (3) barrier dysfunction and increased skin concentrations of brimonidine with increased actions at endothelial and presynaptic receptors, resulting in increased vasodilation; and (4) genetic predisposition and receptor polymorphism(s) leading to different smooth muscle responses. Approximately 80% of patients treated with brimonidine experience a significant improvement without erythema worsening as an adverse event. Attention to optimizing skin barrier function, setting patient expectations, and strategies to minimize potential problems may possibly reduce further the number of patients who experience side effects.

Funding: Galderma International S.A.S., Paris, France.

from Cancer via ola Kala on Inoreader http://ift.tt/2bjv4I7
via IFTTT

Clinicopathological implications of Tiam1 overexpression in invasive ductal carcinoma of the breast

Abstract

Background

T-lymphoma invasion and metastasis-inducing protein 1 (Tiam1) has been implicated in tumor occurrence and progression. Recent studies have shown that high expression levels of Tiam1 protein appear to be associated with the progression of numerous human tumors. This study attempted to explore the role of Tiam1 protein in tumor progression and the prognostic evaluation of breast cancer.

Methods

The localization of the Tiam1 protein was determined in the MDA-MB-231 breast cancer cell line using immunofluorescence (IF) staining. In addition, a total of 283 breast tissue samples, including 153 breast cancer tissues, 67 ductal carcinoma in situ (DCIS) and 63 adjacent non-tumor breast tissues, were analyzed by immunohistochemical (IHC) staining of the Tiam1 protein. The correlation between Tiam1 expression and clinicopathological characteristics was evaluated by Chi-square test and Fisher's exact tests. Disease-free survival (DFS) and 10-year overall survival (OS) rates were calculated by the Kaplan-Meier method. Additionally, univariate and multivariate analyses were performed by the Cox proportional hazards regression models.

Results

Tiam1 protein showed a mainly cytoplasmic staining pattern in breast cancer cells; however, nuclear staining was also observed. Tiam1 protein expression was significantly higher in breast cancers (42.5 %, 65/153) and DCIS (40.3 %, 27/67) than in adjacent non-tumor tissues (12.7 %, 8/63). In addition, Tiam1 associated with tumor stage and Ki-67 expression, but negatively correlated with receptor tyrosine-protein kinase erbB-2 (Her2) expression. Moreover, survival analyses showed that DFS and 10-year OS rates were significantly lower in breast cancer patients with high Tiam1 expression than those with low Tiam1 expression. Univariate analysis suggested that molecular types, clinical stage, Her2 expression levels and Tiam1 expression levels were also significantly associated with DFS and 10-year OS rates of breast cancer patients. Furthermore, multivariate analysis suggested that Tiam1 expression is a significant independent prognostic factor along with tumor stage in patients with breast cancer.

Conclusions

Tiam1 expression is frequently up-regulated in breast cancer. Tiam1 expression correlated with clinicopathological parameters, suggesting that it may be a useful prognostic biomarker and potential therapeutic target for patients with breast cancer.

from Cancer via ola Kala on Inoreader http://ift.tt/2bZfMcU
via IFTTT

NFκB activation demarcates a subset of hepatocellular carcinoma patients for targeted therapy

Abstract

Background

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death worldwide. It is a heterogeneous disorder and >80 % of the tumors develop in patients with liver cirrhosis, resulting from chronic inflammation and/or fibrosis. Here, we set out to identify novel targets for HCC therapy and to define a subgroup of patients that might benefit most from it.

Methods

Cellular pathway activation profiling of 45 transcription factors in a HCC-derived cell line (HEP3B), in vitro analysis of NFκB reporter activity in additional HCC-derived cell lines and pathway-focused integrative analyses of publicly available primary HCC-derived expression profiling data (GSE6764, GSE9843, E-TABM-36 and E-TABM-292) were employed to reveal a role of NFκB in HCC development. In order to identify potential targeting agents, a luciferase-based NFκB reporter screening assay was established in HEP3B cells. After screening of a drug library through this assay, a potent NFκB pathway inhibitor was identified and characterized using an array of additional in vitro assays.

Results

Using cellular pathway activation profiling, we found a high activation of NFκB-mediated signaling in HCC-derived cell lines and in primary HCC tumors. Through NFκB inhibitor screening we observed a highly efficacious NFκB pathway inhibitory potential of ornithogalum in HCC-derived HEP3B cells. Although its active component still remains to be defined, ornithogalum has been found to inhibit endoplasmic reticulum (ER) and oxidative stress responses. ER stress, oxidative stress and NFκB signaling were found to be enhanced in a subset of HCCs, as well as in (precancerous) liver cirrhosis tissues.

Conclusion

From our data we conclude that NFκB signaling is activated in precancerous cirrhosis tissues and in a subset of HCCs. We found that ornithogalum exhibits NFκB targeting and stress relieving activities. NFκB inhibitors, including the active component of ornithogalum, may serve as putative preventive and targeted therapeutic agents for at least a subset of HCCs in which the NFκB pathway is activated. These latter notions require further investigation in a translational context.

from Cancer via ola Kala on Inoreader http://ift.tt/2bCLLMm
via IFTTT

Evaluation of a pediatric fluoroscopy training module to improve performance of upper gastrointestinal procedures in neonates with bilious emesis

Abstract

Background

Life-threatening midgut volvulus usually occurs in infants with malrotation and requires rapid diagnosis and surgical treatment to prevent bowel necrosis and death. However, because of the low frequency of upper gastrointestinal studies performed in infants younger than 1 month, many diagnostic radiology residents finish their residency training having limited or no opportunity to perform or observe an upper gastrointestinal (GI) series for evaluation of bilious emesis in a neonate.

Objective

To determine whether adding simulated upper GI series on neonates with bilious emesis to the curriculum improves residents' skill and accuracy in diagnosing midgut volvulus.

Materials and methods

We assessed the performance of 12 residents in training whose curriculum included simulated upper GI series (study group) and 10 traditionally trained residents (control group) using a multiple-choice test, checklist procedure evaluation and diagnostic accuracy scores for 3 randomly selected simulated upper GI series. We then compared the results from the study group that had simulation curriculum to the scores for the control group using the Mann–Whitney test. We also analyzed the scores for the study group obtained prior to and after simulation curriculum using Wilcoxon signed rank test.

Results

There was a significant difference in test scores (study group median = 84.5%, control group median = 67.2%, P=0.001), overall diagnostic accuracy (study group median = 100%, control group median = 50%, P=0.011) and checklist evaluation (study group median = 83.3%, control group median = 70.8%, P=0.025) for the residents in the study group who completed simulation curriculum compared with the control group. There was also a significant difference in multiple-choice test scores for the study group before and after completion of simulation curriculum (before simulation curriculum median = 56.9%, after simulation curriculum median = 84.5%, P=0.002), checklist evaluation (before simulation curriculum median = 58.3%, after simulation curriculum median = 83.3%, P=0.002) and overall diagnostic accuracy scores (before simulation curriculum median = 50%, after simulation curriculum median = 100%, P=0.024).

Conclusion

Radiology residents had significantly higher scores on a multiple-choice test, checklist procedure evaluation and overall diagnostic accuracy after completing a structured pediatric fluoroscopy curriculum that included simulated neonatal upper GI series and when compared to a control group of traditionally trained residents.

from Cancer via ola Kala on Inoreader http://ift.tt/2bE5zU2
via IFTTT

Quality of life and symptoms in long-term survivors of colorectal cancer: results from NSABP protocol LTS-01

Abstract

Purpose

Little is known about health-related quality of life (HRQL) in long-term survivors (LTS) of colorectal cancer (CRC).

Methods

Long-term CRC survivors (≥5 years) treated in previous National Surgical Adjuvant Breast and Bowel Project trials were recruited from 60 sites. After obtaining consent, a telephone survey was administered, which included HRQL instruments to measure physical health (Instrumental Activities of Daily Living [IADL], SF-12 Physical Component Scale [PCS], SF-36 Vitality Scale), mental health (SF-12 Mental Component Scale [MCS], Life Orientation Test, and Impact of Cancer), and clinical symptoms (Fatigue Symptom Inventory [FSI], European Organization for Research and Treatment of Cancer Colorectal Module [EORTC-CR38], and Brief Pain Inventory). A multivariable model identified predictors of overall quality of life (global health rating).

Results

Participants (N = 708) had significantly higher HRQL compared with age group-matched non-cancer controls with higher mean scores on SF-12 PCS (49.5 vs. 43.7, p = <0.05), MCS (55.6 vs. 52.1, p = <0.05), and SF-36 Vitality Scale (67.1 vs. 59.9, p = <0.05). Multivariable modeling has demonstrated that better overall physical and mental health (PCS and MCS), positive body image (EORTC-CR38 scale), and less fatigue (FSI), were strongly associated with overall quality of life as measured by the global health rating. Interestingly, ability to perform IADLs, experience of cancer, gastrointestinal complaints, and pain, were not important predictors.

Conclusions

In long-term CRC survivors, overall physical and mental health was excellent compared with general population. Other disease-related symptoms did not detract from good overall health.

Implications for cancer survivors

LTS of CRC within the setting of a clinical trial have higher HRQL than the general population, and treatment regimens do not appear to be associated with any significant late effects on quality of life.

Trial Registration: NSABP LTS-01: NCT00410579.

from Cancer via ola Kala on Inoreader http://ift.tt/2bZ5qK9
via IFTTT

Examining the prevalence of metabolic syndrome among overweight/obese African-American breast cancer survivors vs. matched non-cancer controls

Abstract

Purpose

Metabolic Syndrome (MetS) is more predominant in overweight, obese and minority populations. This study examined the prevalence of MetS in an exclusively African-American (AA) cohort of breast cancer (BC) survivors; an underrepresented group in previous studies demonstrating negative BC outcomes disparities for females with MetS.

Methods

Using a case-control design, overweight/obese AA women with treated Stage I–IIIa BC were matched 1:1 on age, race, sex, and body mass index (BMI) category with non-cancer population controls (n = 444). Three of the following conditions were used to define MetS: HDL cholesterol <50 mg/dL (1.3 mmol/L), serum triglycerides ≥150 mg/dL (1.7 mmol/L), blood glucose ≥100 mg/dL (or on treatment), waist circumference ≥88 cm, or ≥130 mmHg systolic or ≥85 mmHg diastolic blood pressure (or on treatment). Matched-pairs analyses were conducted.

Results

For BC cases, most women had self-reported Stage I (n = 76) or Stage II (n = 91) disease and were 6.9 (±5.2) years post-diagnosis. MetS was significantly lower in BC survivors vs. their non-cancer population controls (43.2 vs. 51.4 %, respectively; p < 0.05). The diagnosis of MetS did not differ by BMI stratification. A lower prevalence of ≥2 risk factors (80.2 vs. 85.6 %, p < 0.05) was observed for all cases vs. controls.

Conclusions

While MetS occurred less frequently in our BC cases vs. non-cancer controls, our estimates are nearly two times those reported in other BC survivors, suggesting important racial/ethnic differences.

Implications for cancer survivors

The prognostic implications of MetS among AA BC survivors remain unknown and warrant further investigation.

from Cancer via ola Kala on Inoreader http://ift.tt/2brbDM3
via IFTTT

Current depression as a potential barrier to health care utilization in adult cancer survivors

Publication date: October 2016
Source:Cancer Epidemiology, Volume 44
Author(s): Vinay K. Cheruvu, S.Cristina Oancea
BackgroundDepression in cancer survivors is a major concern and is associated with poor health related quality of life (HRQOL). Delaying or forgoing care due to depression may further augment poor HRQOL. Although several studies have documented depression as a barrier to health care utilization in non-cancer populations, the impact of current depression on health care utilization among adult cancer survivors (ACS) has not been fully elucidated. The objective of this study was to examine the association between current depression and health care utlization among ACS.MethodsData from the 2010 Behavioral Risk Factor Surveillance System involving ACS were used in this study. The Patient Health Questionnaire 8 (PHQ-8) item scale was used to measure current depression. Two indicators of health care utilization were examined as outcomes of interest: cost as a barrier to medical care and not having a routine care. Logistic regression models were used to examine the association between current depression and health care utilization.ResultsOverall, 13.0% of ACS reported symptoms of current depression. Despite no differences in having access to care, current depression in ACS was a significant barrier to health care utilization: cost as a barrier to medical care (AOR: 5.3 [95% CI: 3.1–9.1]), and not having a routine care (AOR: 2.0 [95% CI: 1.2–3.3]).ConclusionsOur findings have implications for future studies to further understand the association between depression and health care utlization among ACS, its impact on their overall wellbeing, and efforts to detect and treat depression in ACS. Routine assessment of depression in ACS and effective treatment interventions may aid in seeking timely and appropriate medical care.



from Cancer via ola Kala on Inoreader http://ift.tt/2bS9Pwr
via IFTTT

MicroRNAs Role as Potential Biomarkers and Key Regulators in Melanoma

Abstract

Malignant melanoma (MM) is a highly aggressive skin cancer with high incidence worldwide. It originates from melanocytes and is characterized by invasion, early metastasis and despite the use of new drugs it is still characterized by high mortality. Since an early diagnosis determines a better prognosis, it is important to explore novel prognostic markers in the management of patients with MM. microRNAs (miRNAs) are small (∼22 nucleotides) single-stranded non-coding RNAs that negatively regulate the expression of more than 60% of human genes.

miRNAs alterations are involved in several cancers, including MM, where a differential expression for some of them has been reported between healthy controls and MM patients. Moreover, since miRNAs are stable and easily detectable in body fluids, they might be considered as robust candidate biomarkers useful to identify risk of MM, to diagnose an early lesion and/or an early metastatic disease. This review highlights the importance of miRNAs as risk factors, prognostic factors and their role as molecular regulator in the development and progression of MM. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2bzTT35
via IFTTT

Preoperative metabolic syndrome and prognosis after radical resection for colorectal cancer: The Fujian prospective investigation of cancer (FIESTA) study

Abstract

This prospective study sought to investigate the prediction of preoperative metabolic syndrome and its components for the risk of colorectal cancer (CRC) mortality by analyzing a subset of data from the ongoing Fujian prospective investigation of cancer (FIESTA) study. In total, 1318 CRC patients who received radical resection were consecutively enrolled between January 2000 and December 2008. The median follow-up time was 58.6 months, with 412 deaths from CRC. The CRC patients with metabolic syndrome had significantly shorter median survival time (MST) than those without (50.9 vs. 170.3 months, P<0.001). Among 4 components of metabolic syndrome, hyperglycemia was the strongest predictor and its presence was associated with shorter MST than its absence (44.4 vs. 170.3 months, P<0.001). Moreover, the complication of metabolic syndrome in CRC patients was associated with a 2.98-fold increased risk of CRC mortality (hazard ratio [HR]=2.98, 95% confidence interval [CI]: 2.40-3.69, P<0.001) after adjusting for confounding factors. The magnitude of this association was especially potentiated in CRC patients with tumor-node-metastasis stage I/II (HR=3.94, 95% CI: 2.65-5.85, P<0.001), invasion depth T1/T2 (HR=5.41, 95% CI: 2.54-11.50, P<0.001), regional lymph node metastasis N0 (HR=4.06, 95% CI: 2.85-5.80, P<0.001) and negative distant metastasis (HR=3.23, 95% CI: 2.53-4.12, P<0.001). Further survival tree analysis reinforced the prognostic capability of fasting blood glucose in CRC survival. Our findings convincingly demonstrated that preoperative metabolic syndrome, especially hyperglycemia, was a robust predictor for CRC mortality, and the protection was more obvious in patients with stage I/II. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2bCMZaq
via IFTTT

Coffee and green tea consumption in relation to brain tumor risk in a Japanese population

Abstract

Few prospective studies have investigated the etiology of brain tumor, especially among Asian populations. Both coffee and green tea are popular beverages, but their relation with brain tumor risk, particularly with glioma, has been inconsistent in epidemiological studies. In this study, we evaluated the association between coffee and greed tea intake and brain tumor risk in a Japanese population.

We evaluated a cohort of 106,324 subjects (50,438 men and 55,886 women) in the Japan Public Health Center-based Prospective Study (JPHC Study). Subjects were followed from 1990 for Cohort I and 1993 for Cohort II until December 31, 2012. 157 (70 men and 87 women) newly diagnosed cases of brain tumor were identified during the study period. Hazard ratio (HR) and 95% confidence intervals (95%CIs) for the association between coffee or green tea consumption and brain tumor risk were assessed using a Cox proportional hazards regression model.

We found a significant inverse association between coffee consumption and brain tumor risk in both total subjects (≥3 cups/day; HR=0.47, 95%CI=0.22-0.98) and in women (≥3 cups/day; HR=0.24, 95%CI=0.06-0.99), although the number of cases in the highest category was small. Furthermore, glioma risk tended to decrease with higher coffee consumption (≥3 cups/day; HR=0.54, 95%CI=0.16-1.80). No association was seen between green tea and brain tumor risk.

In conclusion, our study suggested that coffee consumption might reduce the risk of brain tumor, including that of glioma, in the Japanese population. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2bE1P4Q
via IFTTT

Alternating Electric Fields (TTFields) in Combination with Paclitaxel are Therapeutically Effective against Ovarian Cancer Cells in vitro and in vivo

Abstract

Long-term survival rates for advanced ovarian cancer patients have not changed appreciably over the past four decades; therefore, development of new, effective treatment modalities remains a high priority. Tumor Treating Fields (TTFields), a clinically active anticancer modality utilize low-intensity, intermediate frequency, alternating electric fields. The goal of this study was to evaluate the efficacy of combining TTFields with paclitaxel against ovarian cancer cells in vitro and in vivo. In vitro application of TTFields on human ovarian cancer cell lines led to a significant reduction in cell counts as compared to untreated cells. The effect was found to be frequency and intensity dependent. Further reduction in the number of viable cells was achieved when TTFields treatment was combined with paclitaxel. The in vivo effect of the combined treatment was tested in mice orthotopically implanted with MOSE-L_FFL cells. In this model, combined treatment led to a significant reduction in tumor luminescence and in tumor weight as compared to untreated mice. The feasibility of effective local delivery of TTFields to the human abdomen was examined using finite element mesh simulations performed using the Sim4life software. These simulations demonstrated that electric fields intensities inside and in the vicinity of the ovaries of a realistic human computational phantom are about 1 and 2 V/cm pk-pk, respectively, which is within the range of intensities required for TTFields effect. These results suggest that prospective clinical investigation of the combination of TTFields and paclitaxel is warranted. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2bCLjgQ
via IFTTT

NFκB activation demarcates a subset of hepatocellular carcinoma patients for targeted therapy

Abstract

Background

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death worldwide. It is a heterogeneous disorder and >80 % of the tumors develop in patients with liver cirrhosis, resulting from chronic inflammation and/or fibrosis. Here, we set out to identify novel targets for HCC therapy and to define a subgroup of patients that might benefit most from it.

Methods

Cellular pathway activation profiling of 45 transcription factors in a HCC-derived cell line (HEP3B), in vitro analysis of NFκB reporter activity in additional HCC-derived cell lines and pathway-focused integrative analyses of publicly available primary HCC-derived expression profiling data (GSE6764, GSE9843, E-TABM-36 and E-TABM-292) were employed to reveal a role of NFκB in HCC development. In order to identify potential targeting agents, a luciferase-based NFκB reporter screening assay was established in HEP3B cells. After screening of a drug library through this assay, a potent NFκB pathway inhibitor was identified and characterized using an array of additional in vitro assays.

Results

Using cellular pathway activation profiling, we found a high activation of NFκB-mediated signaling in HCC-derived cell lines and in primary HCC tumors. Through NFκB inhibitor screening we observed a highly efficacious NFκB pathway inhibitory potential of ornithogalum in HCC-derived HEP3B cells. Although its active component still remains to be defined, ornithogalum has been found to inhibit endoplasmic reticulum (ER) and oxidative stress responses. ER stress, oxidative stress and NFκB signaling were found to be enhanced in a subset of HCCs, as well as in (precancerous) liver cirrhosis tissues.

Conclusion

From our data we conclude that NFκB signaling is activated in precancerous cirrhosis tissues and in a subset of HCCs. We found that ornithogalum exhibits NFκB targeting and stress relieving activities. NFκB inhibitors, including the active component of ornithogalum, may serve as putative preventive and targeted therapeutic agents for at least a subset of HCCs in which the NFκB pathway is activated. These latter notions require further investigation in a translational context.

from Cancer via ola Kala on Inoreader http://ift.tt/2bCLLMm
via IFTTT

Measles virus selectively blind to SLAM has oncolytic efficacy against nectin-4-expressing pancreatic cancer cells

Summary

Pancreatic cancer is one of the most intractable cancers and has a devastating prognosis over the past three decades the 5-year survival rate has been less than 10%. Therefore, development of a novel anticancer treatment for pancreatic cancer is a matter of urgency. We previously developed an oncolytic recombinant measles virus (MV), rMV-SLAMblind, which had lost the ability to bind to its principal receptor, signaling lymphocyte activity molecule (SLAM), but which selectively infected and efficiently killed nectin-4-expressing breast and lung cancer cells. In this study, we analyzed the antitumor effect of this virus against pancreatic cancer. Nectin-4 was expressed on the surface of 4/16 tested pancreatic cancer cell lines, which were efficiently infected and killed by rMV-SLAMblind in vitro. The intratumoral inoculation of rMV-SLAMblind suppressed the growth of KLM1 and Capan-2 cells xenografted in SCID mice. The sequence analysis of MV isolated from the tumor revealed that the designed mutation in the H protein of rMV-SLAMblind had been stably maintained for 47 days after the last inoculation. These results suggest that rMV-SLAMblind is a promising candidate for the novel treatment of pancreatic cancer.

This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2bDOCsR
via IFTTT

Expression of metastasis suppressor gene AES driven by a YY element in a CpG island promoter and transcription factor YY2

Abstract

We have recently found that the product of Amino-terminal enhancer of split (AES) gene functions as a metastasis suppressor of colorectal cancer (CRC) in both humans and mice. Expression of AES protein is significantly decreased in liver metastatic lesions compared with primary colon tumors. To investigate its down-regulation mechanism in metastases, we have searched for transcriptional regulators of AES in human CRC, and show that its expression is reduced mainly by transcriptional dysregulation and, in some cases, by additional haploidization of its coding gene. The AES promoter-enhancer is in a typical CpG island, and contains a Yin-Yang transcription-factor recognition sequence (YY element). In human epithelial cells of normal colon and primary tumors, transcription factor YY2, a member of the YY family, binds directly to the YY element, and stimulates expression of AES. In a transplantation mouse model of liver metastases, however, expression of Yy2 (and therefore of Aes) is down-regulated. In human CRC metastases to the liver, the levels of AES protein are correlated with those of YY2. In addition, we noticed copy-number reduction for the AES-coding gene in Chromosome 19p13.3 in 12% (5/42) of human CRC cell lines. We excluded other mechanisms such as point or in-del mutations in the coding or regulatory regions of the AES gene, CpG methylation in the AES promoter-enhancer, expression of microRNAs (miRNAs), chromatin histone modifications etc. These results indicate that Aes may belong to a novel family of metastasis suppressors with a CpG-island promoter-enhancer, and it is regulated transcriptionally.

This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2bCwTgI
via IFTTT

Calreticulin is highly expressed in pancreatic cancer stem-like cells

Abstract

Cancer stem-like cells (CSLCs) in solid tumors are thought to be resistant to conventional chemotherapy or molecular targeting therapy and to contribute to cancer recurrence and metastasis. In this study, we aimed to identify a biomarker of pancreatic CSLCs (P-CSLCs). P-CSLC-enriched population was generated from pancreatic cancer cell lines using our previously reported method and its protein expression profile was compared with that of parental cells by two-dimensional electrophoresis and tandem mass spectrometry. The results indicated that a chaperone protein calreticulin (CRT) was significantly upregulated in P-CSLCs compared to parental cells. Flow cytometry analysis demonstrated that CRT was mostly localized to the surface of P-CSLCs and did not correlate with the levels of CD44v9, another P-CSLC biomarker. Furthermore, the side population in CRT^high/CD44v9^low population is much higher than that in CRT^low/CD44v9^high population. CRT expression was also assessed by immunohistochemistry in pancreatic cancer tissues (n = 80) obtained after radical resection and was found to be associated with patients' clinicopathological features and disease outcomes in the Cox's proportional hazard regression model. Multivariate analysis identified CRT as an independent prognostic factor for pancreatic cancer patients, along with age and post-operative therapy. Our results suggest that CRT can serve as a biomarker of P-CSLCs and a prognostic factor associated with poorer survival of pancreatic cancer patients. This novel biomarker can be considered as a therapeutic target for cancer immunotherapy.

This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2bDPJsl
via IFTTT

Multiple facets of p53 in senescence induction and maintenance

Abstract

Cellular senescence is a state of durable cell cycle arrest with metabolic activities distinct from those of the proliferative state. Since senescence was originally reported to be induced by various genotoxic stressors, such as telomere erosion and oncogenic signaling, it has been proposed to play a pivotal role in aging-related changes and as an anti-tumorigenic barrier in vivo. However, the mechanisms underlying its induction and maintenance remain entirely elusive. We have recently found that abrupt activation of p53 at G2 results in a cell skipping mitosis and subsequently undergoing senescence. Surprisingly, we have also found that downregulation of p53 by SCF^Fbxo22 is crucial for the induction of an senescence-associated phenotype. In this review, we provide an overview of recent advances in understanding the mechanisms underlying the timing and magnitude of activation of p53 during senescence.

This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2bCwSJG
via IFTTT

Inhibiting Autophagy Increases Epirubicin's Cytotoxicity in Breast Cancer Cells

Abstract

Chemotherapy, radiotherapy, and endocrinotherapy are documented to induce autophagy among breast cancer cells, but the role of autophagy in this disease has been attributed to be cytoprotective as well as tumor-suppressing. Thus we studied MDA-MB-231 and SK-BR-3 breast cancer cell lines treated with epirubicin (EPI) to assess autophagy and apoptosis. We found out that EPI induced apoptosis and autophagy in both cell lines, the lysosomal inhibitor bafilomycin A1 (BAF) inhibited cellular autophagy and enhanced EPI-triggered apoptosis perhaps due to inhibition of autolysosome formation, which then inhibited autophagic effects of engulfing and clearing damaged mitochondria. This inhibition increased mitochondrial cytochrome C release which augmented epirubicin-induced caspase-dependent apoptosis and cytotoxicity. Besides, the lysosomal neutralizing agent Ammonia Chloride (AC), and Atg7 knockdown by siRNA, could inhibit Epirubicin-triggered autophagy, enhance cytotoxicity, and increase caspase-9,-3 dependent apoptosis. Thus, autophagy plays a prosurvival role in EPI-treated MDA-MB-231 and SK-BR-3 cells, and autophagy inhibition can potentially reverse this effect and increase EPI's cytotoxicity.

This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2bDQ8Lj
via IFTTT

Long non-coding RNA UCA1 contributes to the progression of oral squamous cell carcinoma via regulating WNT/β-catenin signaling pathway

Abstract

With the development of the functional genomics studies, a mass of long non-coding RNAs (LncRNA) were discovered from the human genome. LncRNAs serve as pivotal regulator of genes, which are able to generate LncRNA-binding-protein complexes to modulate a great many of genes. Recently, the LncRNA urothelial carcinoma-associated 1 (UCA1) has been revealed to be dysregulated, which plays a critical role in the development of a few cancers. However, the role of biology and clinical signification of UCA1 in the tumorigenesis of oral squamous carcinoma (OSCC) remain unknown. Hereof, we found that UCA1 expression levels were upregulated aberrantly in TSCC tissues and associated with lymph node metastasis (LNM) and TNM stage. We explored the expression, function and molecular mechanism of LncRNA-UCA1 in the oral squamous cell carcinoma. In the present work, we demonstrated that UCA1 silencing suppressived the proliferation and metastasis, induced apoptosis of OSCC cell lines in vitro and in vivo, which might be related to the activation level of WNT/β-catenin signaling pathway. To sum up, our research results emphasize the pivotal role of UCA1 in the oncogenesis of OSCC and, revealed a novel LncRNA UCA1-β-catenin-WNT signaling pathway regulatory network, which may contribute to our understanding in the pathogenesis of OSCC and discover a viable LncRNA-directed diagnostic and therapeutic strategy for this fatal disease.

This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2bCxEGF
via IFTTT

Synergistic activity of CARD11 mutant and BCL6 in the development of diffuse large B cell lymphoma in a mouse model

Abstract

Diffuse large B cell lymphoma (DLBCL) is the most common subtype of malignant lymphoma; it derives from germinal center (GC) B cells. Although DLBCL harbors many genetic alterations, synergistic roles between such alterations in the development of lymphoma are largely undefined. We previously established a mouse model of lymphoma by transplanting gene-transduced GC B cells into mice. Here, we chose one of the frequently mutated genes in DLBCL, Card11 mutant, to explore its possible synergy with other genes, employing our lymphoma model. Given that BCL6 and BCL2 expression and/or function are often deregulated in human lymphoma, we examined the possible synergy between Card11, Bcl6, and Bcl2. GC B cells were induced in vitro, transduced with Card11 mutant, Bcl6, and Bcl2, and transplanted. Mice rapidly developed lymphomas, with exogenously transduced Bcl2 being dispensable. Although some mice developed lymphoma in the absence of transduced Bcl6, the absence was compensated by elevated expression of endogenous Bcl6. Additionally, the synergy between Card11 mutant and Bcl6 in the development of lymphoma was confirmed by the fact that the combination of Card11 mutant and Bcl6 caused lymphoma or death significantly earlier and with higher penetrance than Card11 mutant or Bcl6 alone. Lymphoma cells expressed IRF4 and PRDM1, indicating their differentiation toward plasmablasts, which characterize activated B cell-like DLBCL that represents a clinically aggressive subtype in humans. Thus, our mouse model provides a versatile tool for studying the synergistic roles of altered genes, underlying lymphoma development.

This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2bDPcH7
via IFTTT

Poor compliance with adjuvant chemotherapy use associated with poorer survival in patients with rectal cancer: An NCDB analysis

BACKGROUND

National Comprehensive Cancer Network treatment guidelines for patients with locally advanced rectal cancer include neoadjuvant chemoradiation followed by total mesorectal excision and adjuvant chemotherapy. The objective of the current study was to examine the rate of adjuvant chemotherapy and associated survival in patients with stage II/III rectal cancer.

METHODS

The 2006 to 2011 National Cancer Data Base was queried for patients with AJCC clinical stage II/III rectal cancer who underwent neoadjuvant chemoradiation and surgical resection. A mixed effects multivariable logistic regression identified factors associated with the receipt of adjuvant chemotherapy. A mixed effects Cox proportional hazards model was used to estimate the adjusted effect of receiving adjuvant therapy on 5-year overall survival (OS).

RESULTS

A total of 14,742 patients were included; 68% of the cohort did not receive adjuvant chemotherapy. When controlled for clinical stage of disease, patients who were aged >70 years, had a higher comorbidity score, and had a pathologic complete response had lower odds of receiving adjuvant therapy. There was a 22-fold difference in the risk-adjusted rate of adjuvant therapy use among hospitals (3.1%-67.7%). Adjuvant therapy was associated with increased 5-year OS when controlled for patient factors, stage of disease, and pathologic response (hazard ratio, 0.65; 95% confidence interval, 0.59-0.71). The greatest survival benefit was noted among patients who achieved a pathologic complete response (hazard ratio, 0.40; 95% confidence interval, 0.23-0.67).

CONCLUSIONS

There is poor compliance to National Comprehensive Cancer Network guidelines for adjuvant chemotherapy in patients with locally advanced rectal cancer after neoadjuvant chemoradiation and surgery. Adjuvant therapy appears to be independently associated with improved OS regardless of stage of disease, pathologic response, and patient factors. The greatest survival benefit was observed in patients who were complete responders. Age and comorbidities were found to be significantly associated with nonreceipt of adjuvant therapy. Improved rehabilitation and physical conditioning may improve the odds of patients receiving adjuvant therapy. Cancer 2016. © 2016 American Cancer Society.

from Cancer via ola Kala on Inoreader http://ift.tt/2bYLKWU
via IFTTT

Association between duration and type of Androgen Deprivation Therapy and risk of diabetes in men with prostate cancer

Abstract

Androgen deprivation therapy (ADT) for prostate cancer (PCa) increases risk of type 2 diabetes (T2DM); however the association between types and duration of ADT has not been fully elucidated. We examined how type and duration of ADT affects risk of T2DM.

Using data from Prostate Cancer database Sweden (PCBaSe) we investigated risk of T2DM in a cohort of 34,031 men with PCa on ADT; i.e. anti-androgens (AA), orchiectomy, or gonadotropin-releasing hormone (GnRH) agonists compared to an age-matched, PCa-free comparison cohort (n=167,205) using multivariate Cox proportional hazard regression. T2DM was defined as a newly filled prescription for metformin, sulphonylurea or insulin in the Prescribed Drug Register.

A total of 21,874 men with PCa received GnRH agonists, 9,143 AA and 3,014 underwent orchiectomy. Risk of T2DM was increased in men in the GnRH agonists/orchiectomy group during the first 3 years of ADT [i.e.1-1.5 years HR: 1.61 (95%CI: 1.36-1.91)], compared to PCa-free men. The risk decreased thereafter (e.g 3-4 years HR: 1.17 (95% CI: 0.98-1.40)). Conversely, no increased risk was seen in men on AA (HR: 0.74 (95%CI: 0.65-0.84). The incidence of T2DM per 1,000 person-years was 10 for PCa-free men, 8 for men on AA, and 13 for men on GnRH agonists/orchiectomy.

Duration of ADT has a significant impact on risk of T2DM. With the peak after three years of treatment, our data indicates that men on ADT, even for a limited period of time, such as adjuvant to radiotherapy, are at increased risk of T2DM. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2bl0v1v
via IFTTT

TRAIL Delivered by Mesenchymal Stromal/Stem Cells Counteracts Tumor Development in Orthotopic Ewing Sarcoma Models

Abstract

Ewing sarcoma (EWS) is the second most frequent pediatric malignant bone tumor. EWS patients have not seen any major therapeutic progress in the last thirty years, in particular in the case of metastatic disease, which requires new therapeutic strategies. The pro-apoptotic cytokine TNF-Related Apoptosis Inducing Ligand (TRAIL) can selectively kill tumor cells while sparing normal cells, making it a promising therapeutic tool in several types of cancer. However, certain EWS cell lines appear resistant to recombinant human (rh) TRAIL-induced apoptosis. We therefore hypothesized that a TRAIL presentation at the surface of the carrier cells might overcome this resistance and trigger apoptosis. For this purpose, human adipose mesenchymal stromal/stem cells (MSC) transfected in a stable manner to express full-length human TRAIL were co-cultured with several human EWS cell lines, inducing apoptosis by cell-to-cell contact even in cell lines initially resistant to rhTRAIL or AMG655, an antibody agonist to the death receptor, DR5. In vivo, TRAIL delivered by MSCs was able to counteract tumor progression in two orthotopic models of Ewing sarcoma, associated with caspase activation, indicating that a cell-based delivery of a potent apoptosis-inducing factor could be relevant in EWS. This article is protected by copyright. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2biHa48
via IFTTT

The impact of positron emission tomography on primary tumour delineation and dosimetric outcome in intensity modulated radiotherapy of early T-stage nasopharyngeal carcinoma

In intensity modulated radiotherapy (IMRT) of nasopharyngeal carcinoma (NPC), accurate delineation of the gross tumour volume (GTV) is important. Image registration of CT and MRI has been routinely used in tre...

from Cancer via ola Kala on Inoreader http://ift.tt/2bQFtJi
via IFTTT

Structure-function relationship of the mammarenavirus envelope glycoprotein

Abstract

Mammarenaviruses, including lethal pathogens such as Lassa virus and Junín virus, can cause severe hemorrhagic fever in humans. Entry is a key step for virus infection, which starts with binding of the envelope glycoprotein (GP) to receptors on target cells and subsequent fusion of the virus with target cell membranes. The GP precursor is synthesized as a polypeptide, and maturation occurs by two cleavage events, yielding a tripartite GP complex (GPC) formed by a stable signal peptide (SSP), GP1 and GP2. The unique retained SSP interacts with GP2 and plays essential roles in virion maturation and infectivity. GP1 is responsible for binding to the cell receptor, and GP2 is a class I fusion protein. The native structure of the tripartite GPC is unknown. GPC is critical for the receptor binding, membrane fusion and neutralization antibody recognition. Elucidating the molecular mechanisms underlining the structure–function relationship of the three subunits is the key for understanding their function and can facilitate novel avenues for combating virus infections. This review summarizes the basic aspects and recent research of the structure–function relationship of the three subunits. We discuss the structural basis of the receptor-binding domain in GP1, the interaction between SSP and GP2 and its role in virion maturation and membrane fusion, as well as the mechanism by which glycosylation stabilizes the GPC structure and facilitates immune evasion. Understanding the molecular mechanisms involved in these aspects will contribute to the development of novel vaccines and treatment strategies against mammarenaviruses infection.

from Cancer via ola Kala on Inoreader http://ift.tt/2biyw5t
via IFTTT