Helicobacter pylori promotes angiogenesis depending on Wnt/beta-catenin-mediated vascular endothelial growth factor via the cyclooxygenase-2 pathway in gastric cancer

Abstract

Background

Helicobacter pylori is an important pathogenic factor in gastric carcinogenesis. Angiogenesis (i.e., the growth of new blood vessels) is closely associated with the incidence and development of gastric cancer. Our previous study found that COX-2 stimulates gastric cancer cells to induce expression of the angiogenic growth factor VEGF through an unknown mechanism. Therefore, the aim of this study was to clarify the role of angiogenesis in H. pylori-induced gastric cancer development.

Methods

To clarify the relationship between H. pylori infection and angiogenesis, we first investigated H. pylori colonization, COX-2, VEGF, beta-catenin expression, and microvessel density (MVD) in gastric cancer tissues from 106 patients. In addition, COX-2, phospho-beta-catenin, and beta-catenin expression were measured by western blotting, and VEGF expression was measured by ELISA in H. pylori-infected SGC7901 and MKN45 human gastric cancer cells.

Results

H. pylori colonization occurred in 36.8 % of gastric carcinoma samples. Furthermore, COX-2, beta-catenin, and VEGF expression, and MVD were significantly higher in H. pylori-positive gastric cancer tissues than in H. pylori-negative gastric cancer tissues (P < 0.01). H. pylori infection was not related to sex or age in gastric cancer patients, but correlated with the depth of tumor invasion, lymph node metastasis, and tumor–node–metastasis stage (P < 0.05) and correlated with the COX-2 expression and beta-catenin expression(P < 0.01). Further cell experiments confirmed that H. pylori infection upregulated VEGF in vitro. Further analysis revealed that H. pylori-induced VEGF expression was mediated by COX-2 via activation of the Wnt/beta-catenin pathway.

Conclusions

The COX-2/Wnt/beta-catenin/VEGF pathway plays an important role in H. pylori-associated gastric cancer development. The COX-2/Wnt/beta-catenin pathway is therefore a novel therapeutic target for H. pylori-associated gastric cancers.

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Primary Gonadal Insufficiency in Male and Female Childhood Cancer Survivors in a Long-Term Follow-Up Clinic

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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Institutional Enrollment and Survival Among NSCLC Patients Receiving Chemoradiation: NRG Oncology Radiation Therapy Oncology Group (RTOG) 0617

Background: The purpose of this analysis is to evaluate the effect of institutional accrual volume on clinical outcomes among patients receiving chemoradiation for locally advanced non–small cell lung cancer (LA-NSCLC) on a phase III trial.

Methods: Patients with LA-NSCLC were randomly assigned to 60 Gy or 74 Gy radiotherapy (RT) with concurrent carboplatin/paclitaxel +/- cetuximab on NRG Oncology RTOG 0617. Participating institutions were categorized as low-volume centers (LVCs) or high-volume centers (HVCs) according to the number of patients accrued (≤3 vs > 3). All statistical tests were two-sided.

Results: Range of accrual for LVCs (n = 195) vs HVCs (n = 300) was 1 to 3 vs 4 to 18 patients. Baseline characteristics were similar between the two cohorts. Treatment at a HVC was associated with statistically significantly longer overall survival (OS) and progression-free survival (PFS) compared with treatment at a LVC (median OS = 26.2 vs 19.8 months; HR = 0.70, 95% CI = 0.56 to 0.88, P = .002; median PFS: 11.4 vs 9.7 months, HR = 0.80, 95% CI = 0.65-0.99, P = .04). Patients treated at HVCs were more often treated with intensity-modulated RT (54.0% vs 39.5%, P = .002), had a lower esophageal dose (mean = 26.1 vs 28.0 Gy, P = .03), and had a lower heart dose (median = V5 Gy 38.2% vs 54.1%, P = .006; V50 Gy 3.6% vs 7.3%, P < .001). Grade 5 adverse events (AEs) (5.3% vs 9.2%, P = .09) and RT termination because of AEs (1.3% vs 4.1%, P = .07) were less common among patients treated at HVCs. HVC remained independently associated with longer OS (P = .03) when accounting for other factors.

Conclusion: Treatment at institutions with higher clinical trial accrual volume is associated with longer OS among patients with LA-NSCLC participating in a phase III trial.

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Lung Cancer Patient Outcomes Better At High-Volume Treatment Centers Than Low-Volume Treatment Centers

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Clinical Proteomics to Catalyze the Cancer Moonshot Program

The Cancer Moonshot Program has been launched and represents a potentially paradigm-shifting initiative with the goal to implement a focused national effort to double the rate of progress against cancer. The placement of precision medicine, immunotherapy, genomics, and combination therapies was placed at the central nexus of this initiative. While we are extremely enthusiastic about the goals of the program, it is time we meet this revolutionary project with equally bold and cutting-edge ideas: its time we move firmly into the post-genome era and provide the necessary resources to propel and seize on innovative recent gains in the field of proteomics required for it to stand on equal footing in this narrative as a combined, synergistic engine for molecular profiling. After all, while the genome is the information archive, it is the proteins that actually do the work of the cell and represent the structural cellular machinery. It is the proteins that comprise most of the biomarkers that are measured to detect cancers, constitute the antigens that drive immune response and inter and itntracellular communications, and it is the proteins that are the drug targets for nearly every targeted therapy that is being evaluated in cancer trials today. We believe that a combined systems biology view of the tumor microenvironment that orients cancer studies back to the functional proteome, phosphoproteome and biochemistry of the cell will be essential to deliver on the promise of the Cancer Moonshot program.

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DNA damage foci persist after low-dose radiation

Purpose:Intensity-modulated radiotherapy (IMRT) enables the delivery of high doses to target volume while sparing surrounding non-targeted tissues. IMRT treatment, however, substantially increases the normal-tissue volume receiving low-dose irradiation, but the biological consequences are unclear. Experimental Design:Using mouse strains that varied in genetic DNA repair capacity, we investigated the DNA damage response of cortical neurons during daily low-dose irradiation (0.1 Gy). Using light and electron microscopic approaches, we enumerated and characterized DNA damage foci as marker for double-strand breaks (DSBs). Results:During repeated low-dose irradiation, cortical neurons in brain tissues of all mouse strains had a significant increase of persisting foci with cumulative doses, with the most pronounced accumulation of large-sized foci in repair-deficient mice. Electron microscopic analysis revealed that persisting foci in repair-proficient neurons reflect chromatin alterations in heterochromatin, but not persistently unrepaired DSBs. Repair-deficient SCID neurons, by contrast, showed high numbers of unrepaired DSBs in eu- and heterochromatin, emphasizing the fundamental role of DNA-PKcs in DSB rejoining, independent of chromatin status. In repair-deficient ATM-/- neurons, large persisting damage foci reflect multiple unrepaired DSBs concentrated at the boundary of heterochromatin due to disturbed KAP1-phosphorylation. Conclusions:Repeated low-dose irradiation leads to the accumulation of persisting DNA damage foci in cortical neurons, and thus may adversely affect brain tissue and increase the risk of carcinogenesis. Multiple unrepaired DSBs account for large-sized foci in repair-deficient neurons, thus quantifying foci alone may underestimate extent and complexity of persistent DNA damage.

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Fertility preservation option in young women with ovarian cancer

Future Oncology Ahead of Print.


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Is mucin a determinant of peritoneal dissemination of gastrointestinal cancer? Analysis of mucin depletion in two preclinical models

Abstract

Background

Mucinous gastrointestinal cancers may indicate a higher propensity for widespread peritoneal seeding than their non-mucinous counterparts. We hypothesized that mucin content of gastrointestinal cancer cells and tumors is an indicator of cell viability and a determinant of the peritoneal tumor burden and tested our hypothesis in relevant experimental models.

Methods

MKN45 and LS174T models of human gastrointestinal cancer were treated with known mucin-depleting agents in vitro and in vivo, their mucin production was evaluated with Western blot immunohistochemistry, PAS staining and ELISA, and its correlation with cell viability and peritoneal tumor burden was analyzed.

Results

A relationship was found between the viability of cancer cells and their mucin levels in vitro. In agreement, when treated animal models were categorized into low- and high-burden groups (based on the weight and number of the peritoneal nodules), tumoral mucin levels were found to be significantly higher in the latter group.

Conclusions

Tumoral mucin is apparently among the factors that dictate the pattern and extent of the peritoneal spread of gastrointestinal cancer, where it allows for enhanced dissemination and redistribution. If further tested and validated, our hypothesis could lay the basis for the development of novel mucin-targeted strategies.

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Interfraction Anatomical Variability Can Lead to Significantly Increased Rectal Dose for Patients Undergoing Stereotactic Body Radiotherapy for Prostate Cancer

Stereotactic body radiotherapy for prostate cancer is rapidly growing in popularity. Stereotactic body radiotherapy plans mimic those of high-dose rate brachytherapy, with tight margins and inhomogeneous dose distributions. The impact of interfraction anatomical changes on the dose received by organs at risk under these conditions has not been well documented. To estimate anatomical variation during stereotactic body radiotherapy, 10 patients were identified who received a prostate boost using robotic stereotactic body radiotherapy after completing 25 fractions of pelvic radiotherapy with daily megavoltage computed tomography. Rectal and bladder volumes were delineated on each megavoltage computed tomography, and the stereotactic body radiotherapy boost plan was registered to each megavoltage computed tomography image using a point-based rigid registration with 3 fiducial markers placed in the prostate. The volume of rectum and bladder receiving 75% of the prescription dose (V75%) was measured for each megavoltage computed tomography. The rectal V75% from the daily megavoltage computed tomographies was significantly greater than the planned V75% (median increase of 0.93 cm³, P < .001), whereas the bladder V75% on megavoltage computed tomography was not significantly changed (median decrease of –0.12 cm³, P = .57). Although daily prostate rotation was significantly correlated with bladder V75% (Spearman = .21, P = .023), there was no association between rotation and rectal V75% or between prostate deformation and either rectal or bladder V75%. Planning organ-at-risk volume-based replanning techniques using either a 6-mm isotropic expansion of the plan rectal contour or a 1-cm expansion from the planning target volume in the superior and posterior directions demonstrated significantly improved rectal V75% on daily megavoltage computed tomographies compared to the original stereotactic body radiotherapy plan, without compromising plan quality. Thus, despite tight margins and full translational and rotational corrections provided by robotic stereotactic body radiotherapy, we find that interfraction anatomical variations can lead to a substantial increase in delivered rectal doses during prostate stereotactic body radiotherapy. A planning organ-at-risk volume-based approach to treatment planning may help mitigate the impact of daily organ motion and reduce the risk of rectal toxicity.

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Fertility preservation option in young women with ovarian cancer

Future Oncology Ahead of Print.


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p62, Upregulated during Preneoplasia, Induces Hepatocellular Carcinogenesis by Maintaining Survival of Stressed HCC-Initiating Cells

Publication date: Available online 19 May 2016
Source:Cancer Cell
Author(s): Atsushi Umemura, Feng He, Koji Taniguchi, Hayato Nakagawa, Shinichiro Yamachika, Joan Font-Burgada, Zhenyu Zhong, Shankar Subramaniam, Sindhu Raghunandan, Angeles Duran, Juan F. Linares, Miguel Reina-Campos, Shiori Umemura, Mark A. Valasek, Ekihiro Seki, Kanji Yamaguchi, Kazuhiko Koike, Yoshito Itoh, Maria T. Diaz-Meco, Jorge Moscat, Michael Karin
p62 is a ubiquitin-binding autophagy receptor and signaling protein that accumulates in premalignant liver diseases and most hepatocellular carcinomas (HCCs). Although p62 was proposed to participate in the formation of benign adenomas in autophagy-deficient livers, its role in HCC initiation was not explored. Here we show that p62 is necessary and sufficient for HCC induction in mice and that its high expression in non-tumor human liver predicts rapid HCC recurrence after curative ablation. High p62 expression is needed for activation of NRF2 and mTORC1, induction of c-Myc, and protection of HCC-initiating cells from oxidative stress-induced death.

Graphical abstract

Teaser

Umemura et al. employ several mouse models of HCC to demonstrate that p62 facilitates activation of NRF2 and mTORC1 and is essential for HCC initiation. High levels of p62 accumulation in non-tumor liver tissue in early-stage HCC patients undergoing curative ablation correlates with reduced overall survival.


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Pulmonary arterial hypertension in children: diagnosis using ratio of main pulmonary artery to ascending aorta diameter as determined by multi-detector computed tomography

Abstract

Background

The ratio of the transverse diameter of the main pulmonary artery (MPA) to ascending aorta as determined at multi-detector CT is a tool that can be used to assess the pulmonary arterial size in cases of pulmonary arterial hypertension in children.

Objective

To establish a ratio of MPA to ascending aorta diameter using multi-detector CT imaging suggestive of pulmonary arterial hypertension in children. We hypothesize that a defined ratio of MPA to ascending aorta is identifiable on multi-detector CT and that higher ratios can be used to reliably diagnose the presence of pulmonary arterial hypertension in children.

Materials and methods

We calculated the multi-detector CT ratio of MPA to ascending aorta diameter in 44 children with documented pulmonary arterial hypertension by right heart catheterization and in 44 age- and gender-matched control children with no predisposing factors for pulmonary arterial hypertension. We compared this multi-detector-CT-determined ratio with the MPA pressure in the study group, as well as with the ratio of MPA to ascending aorta in the control group. A threshold ratio value was calculated to accurately identify children with pulmonary arterial hypertension.

Results

Children with documented primary pulmonary arterial hypertension have a significantly higher ratio of MPA to ascending aorta (1.46) than children without pulmonary arterial hypertension (1.11). A ratio of 1.3 carries a positive likelihood (of 34 and a positive predictive value of 97%) for the diagnosis of pulmonary arterial hypertension.

Conclusion

The pulmonary arteries were larger in children with pulmonary arterial hypertension than in a control group of normal children. A CT-measured ratio of MPA to ascending aorta of 1.3 should raise the suspicion of pulmonary arterial hypertension in children.

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Diagnostic Accuracy of BRAF Immunohistochemistry in Colorectal Cancer: a Meta-Analysis and Diagnostic Test Accuracy Review

Abstract

The aim of this study was to evaluate the concordance between the BRAF ^V600E mutation test and immunohistochemistry (IHC) and to evaluate the diagnostic accuracy of BRAF IHC for colorectal cancer (CRC) through a systematic review, meta-analysis, and diagnostic test accuracy review. The current study included 1021 CRCs from eight eligible studies. The concordance rates were investigated between BRAF IHC and the mutation test. In addition, diagnostic test accuracy review was conducted and calculated using the value of area under curve (AUC) on the summary receiver operating characteristic (SROC) curve. The positive rate of BRAF IHC was 30.5 % (range; 13.2–66.2 %), and the BRAF mutation was found in 30.2 % (range; 11.7–66.2 %). The overall concordance rate between BRAF IHC and the mutation test was 0.944 (95 % confidence interval (CI) 0.873–0.977). In the BRAF IHC-positive and -negative groups, the concordance rates between BRAF IHC and the mutation test were 0.895 (95 % CI 0.800–0.945) and 0.956 (95 % CI 0.878–0.985), respectively. The pooled sensitivity and specificity were 0.94 (95 % CI 0.91–0.96) and 0.96 (95 % CI 0.95–0.98), respectively. The diagnostic odds ratio was 272.86 (95 % CI 46.11–1614.88), and the value of AUC on SROC curve was 0.9846. Taken together, our results suggest that BRAF IHC is strongly concordant with the BRAF mutation test and has high diagnostic accuracy in BRAF mutation analysis of CRCs. Further cumulative studies on detailed evaluation criteria are needed before application in daily practice.

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Microsurgical removal of craniopharyngioma: endoscopic and transcranial techniques for complication avoidance

Abstract

Craniopharyngioma remains a challenging entity for neurosurgeons because of its midline, deep seated location and intimate relationship with critical neurovascular structures. Although gross total resection is ideal, the need to reduce surgical morbidity and preserve quality of life has led to a number of neurosurgical approaches which have attained this goal. Here we discuss the commonly used approaches for surgical resection and highlight technical considerations to reduce the potential of complications. We also discuss the mutually exclusive underlying genetic lesions in different histopathological subtypes that will likely lead to future treatment options for these tumors.

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Microsurgical resection of pineal region tumors

Abstract

The extensive variety of possible histologic subtypes makes it imperative to establish a tissue diagnosis in patients with pineal region tumors. Management decisions regarding adjuvant therapy, prognosis, and follow-up strategies vary with the histologic diagnosis. Specialized surgical and stereotactic techniques have evolved to provide the neurosurgeon with an array of safe and effective options for obtaining a tissue diagnosis. Advanced microsurgical techniques combined with improved preoperative management and postoperative critical care methods have made aggressive surgical resection a mainstay of management. Aggressive surgical resection has resulted in excellent long-term prognoses for nearly all patients with benign tumors and a large percentage of patients with malignant tumors. However, pineal region surgery remains fraught with potential pitfalls, and these favorable results are dependent on an advanced level of surgical expertise.

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Cancer Incidence among Heart, Kidney, and Liver Transplant Recipients in Taiwan

by Kwai-Fong Lee, Yi-Ting Tsai, Chih-Yuan Lin, Chung-Bao Hsieh, Sheng-Tang Wu, Hung-Yen Ke, Yi-Chang Lin, Feng-Yen Lin, Wei-Hwa Lee, Chien-Sung Tsai

Population-based evidence of the relative risk of cancer among heart, kidney, and liver transplant recipients from Asia is lacking. The Taiwan National Health Insurance Research Database was used to conduct a population-based cohort study of transplant recipients (n = 5396), comprising 801 heart, 2847 kidney, and 1748 liver transplant recipients between 2001 and 2012. Standardized incidence ratios and Cox regression models were used. Compared with the general population, the risk of cancer increased 3.8-fold after heart transplantation, 4.1-fold after kidney transplantation and 4.6-fold after liver transplantation. Cancer occurrence showed considerable variation according to transplanted organs. The most common cancers in all transplant patients were cancers of the head and neck, liver, bladder, and kidney and non-Hodgkin lymphoma. Male recipients had an increased risk of cancers of the head and neck and liver, and female kidney recipients had a significant risk of bladder and kidney cancer. The adjusted hazard ratio for any cancer in all recipients was higher in liver transplant recipients compared with that in heart transplant recipients (hazard ratio = 1.5, P = .04). Cancer occurrence varied considerably and posttransplant cancer screening should be performed routinely according to transplanted organ and sex.

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Microsurgical removal of craniopharyngioma: endoscopic and transcranial techniques for complication avoidance

Abstract

Craniopharyngioma remains a challenging entity for neurosurgeons because of its midline, deep seated location and intimate relationship with critical neurovascular structures. Although gross total resection is ideal, the need to reduce surgical morbidity and preserve quality of life has led to a number of neurosurgical approaches which have attained this goal. Here we discuss the commonly used approaches for surgical resection and highlight technical considerations to reduce the potential of complications. We also discuss the mutually exclusive underlying genetic lesions in different histopathological subtypes that will likely lead to future treatment options for these tumors.

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Low WT1 transcript levels at diagnosis predicted poor outcomes of acute myeloid leukemia patients with t(8;21) who received chemotherapy or allogeneic hematopoietic stem cell transplantation

Abstract

Background

Acute myeloid leukemia (AML) with t(8;21) is a heterogeneous disease. Identifying AML patients with t(8;21) who have a poor prognosis despite achieving remission is important for determining the best subsequent therapy. This study aimed to evaluate the impact of Wilm tumor gene-1 (WT1) transcript levels and cellular homolog of the viral oncogene v-KIT receptor tyrosine kinase (C-KIT) mutations at diagnosis, and RUNX1-RUNX1T1 transcript levels after the second consolidation chemotherapy cycle on outcomes.

Methods

Eighty-eight AML patients with t(8;21) who received chemotherapy only or allogeneic hematopoietic stem cell transplantation (allo-HSCT) were included. Patients who achieved remission, received two or more cycles of consolidation chemotherapy, and had a positive measureable residual disease (MRD) test result (defined as <3-log reduction in RUNX1-RUNX1T1 transcript levels compared to baseline) after 2–8 cycles of consolidation chemotherapy were recommended to receive allo-HSCT. Patients who had a negative MRD test result were recommended to receive further chemotherapy up to only 8 cycles. WT1 transcript levels and C-KIT mutations at diagnosis, and RUNX1-RUNX1T1 transcript levels after the second consolidation chemotherapy cycle were tested.

Results

Patients who had a C-KIT mutation had significantly lower WT1 transcript levels than patients who did not have a C-KIT mutation (6.7% ± 10.6% vs. 19.5% ± 19.9%, P < 0.001). Low WT1 transcript levels (≤5.0%) but not C-KIT mutation at diagnosis, a positive MRD test result after the second cycle of consolidation chemotherapy, and receiving only chemotherapy were independently associated with high cumulative incidence of relapse in all patients (hazard ratio [HR] = 3.53, 2.30, and 11.49; 95% confidence interval [CI] 1.64–7.62, 1.82–7.56, and 4.43–29.82; P = 0.002, 0.034, and <0.001, respectively); these conditions were also independently associated with low leukemia-free survival (HR = 3.71, 2.33, and 5.85; 95% CI 1.82–7.56, 1.17–4.64, and 2.75–12.44; P < 0.001, 0.016, and <0.001, respectively) and overall survival (HR = 3.50, 2.32, and 4.34; 95% CI 1.56–7.82, 1.09–4.97, and 1.98–9.53; P = 0.002, 0.030, and <0.001, respectively) in all patients.

Conclusions

Testing for WT1 transcript levels at diagnosis in patients with AML and t(8;21) may predict outcomes in those who achieve remission. A randomized study is warranted to determine whether allo-HSCT can improve prognosis in these patients.

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Is mucin a determinant of peritoneal dissemination of gastrointestinal cancer? Analysis of mucin depletion in two preclinical models

Abstract

Background

Mucinous gastrointestinal cancers may indicate a higher propensity for widespread peritoneal seeding than their non-mucinous counterparts. We hypothesized that mucin content of gastrointestinal cancer cells and tumors is an indicator of cell viability and a determinant of the peritoneal tumor burden and tested our hypothesis in relevant experimental models.

Methods

MKN45 and LS174T models of human gastrointestinal cancer were treated with known mucin-depleting agents in vitro and in vivo, their mucin production was evaluated with Western blot immunohistochemistry, PAS staining and ELISA, and its correlation with cell viability and peritoneal tumor burden was analyzed.

Results

A relationship was found between the viability of cancer cells and their mucin levels in vitro. In agreement, when treated animal models were categorized into low- and high-burden groups (based on the weight and number of the peritoneal nodules), tumoral mucin levels were found to be significantly higher in the latter group.

Conclusions

Tumoral mucin is apparently among the factors that dictate the pattern and extent of the peritoneal spread of gastrointestinal cancer, where it allows for enhanced dissemination and redistribution. If further tested and validated, our hypothesis could lay the basis for the development of novel mucin-targeted strategies.

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Inflammatory insult during pregnancy accelerates age-related behavioral and neurobiochemical changes in CD-1 mice

Abstract

Data shows that inflammation during pregnancy significantly exerts a long-term influence on offspring, such as increasing the risk of adult cognition decline in animals. However, it is unclear whether gestational inflammation affects the neurobehavioral and neurobiochemical outcomes in the mother-self during aging. In this study, pregnant CD-1 mice intraperitoneally received lipopolysaccharide (LPS) in two doses (25 and 50 g/kg, respectively) or normal saline daily during gestational days 15–17. At the age of 15 months, a battery of behavioral tasks was employed to evaluate their species-typical behaviors, sensorimotor ability, anxiety levels, and spatial learning and memory abilities. An immunohistochemical method was utilized preliminarily to detect neurobiochemical indicators consisting of amyloid-β, phosphorylated tau, presynaptic proteins synaptotagmin-1 and syntaxin-1, glial fibrillary acidic protein (GFAP), and histone-4 acetylation on the K8 site (H4K8ac). The behavioral results showed that LPS exposure during pregnancy exacerbated a decline in 15-month-old CD-1 mice's abilities to nest, their sensorimotor and spatial learning and memory capabilities, and increased their anxiety levels. The neurobiochemical results indicated that gestational LPS exposure also intensified age-related hippocampal changes, including increased amyloid-β₄₂, phosphorylated tau, synaptotagmin-1 and GFAP, and decreased syntaxin-1 and H4K8ac. Our results suggested that the inflammatory insult during pregnancy could be an important risk factor for the development of Alzheimer's disease, and the H4K8 acetylation might play an important role in the underlying mechanism. This study offers a perspective for improving strategies that support healthy development and successful aging.

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Determining predictive factors for immune checkpoint inhibitor toxicity: Response to Letter to the Editors “A case report of insulin-dependent diabetes as immune-related toxicity of pembrolizumab: presentation, management and outcome”

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Peer-counseling for women newly diagnosed with breast cancer: A randomized community/research collaboration trial

BACKGROUND

We conducted a randomized controlled trial of peer-counseling for newly diagnosed breast cancer (BC) patients as a community/research collaboration testing an intervention developed jointly by a community-based-organization serving women with cancer and university researchers.

METHODS

We recruited 104 women newly diagnosed with BC at any disease stage. Prior to randomization, all received a one-time visit with an oncology nurse who offered information and resources. Afterwards, we randomized half to receive a match with a Navigator with whom they could have contact for up to 6 months. We recruited, trained, and supervised 30 peer counselors who became "Navigators." They were at least one-year post-diagnosis with BC. Controls received no further intervention. We tested the effect of intervention on breast-cancer–specific well-being and trauma symptoms as primary outcomes, and several secondary outcomes. In exploratory analyses, we tested whether responding to their diagnosis as a traumatic stressor moderated outcomes.

RESULTS

We found that, compared with the control group, receiving a peer-counseling intervention significantly improved breast-cancer–specific well-being (p=0.01, Cohen's d=0.41) and maintained marital adjustment (p=0.01, Cohen's d=0.45) more effectively. Experiencing the diagnosis as a traumatic stressor moderated outcomes: those with a peer counselor in the traumatic stressor group improved significantly more than controls on well-being, trauma and depression symptoms, and cancer self-efficacy.

CONCLUSIONS

Having a peer counselor trained and supervised to recognize and work with trauma symptoms can improve well-being and psychosocial morbidity during the first year following diagnosis of BC. Cancer 2016. © 2016 American Cancer Society.

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Reply to the association between religion/spirituality and mental health in cancer

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The association between religion/spirituality and mental health in cancer

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A phase 1 study of buparlisib and bevacizumab in patients with metastatic renal cell carcinoma progressing on vascular endothelial growth factor-targeted therapies

BACKGROUND

The phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is dysregulated in patients with metastatic renal cell carcinoma (mRCC). Buparlisib is a pan-PI3K inhibitor with activity in advanced solid tumors. The primary objective of the current study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of buparlisib and bevacizumab in patients with mRCC. Secondary objectives included efficacy, biomarker discovery, and additional toxicity.

METHODS

This was a standard 3 + 3 dose escalation study of buparlisib (at a dose of 60-100 mg/day) and bevacizumab (at a dose of 10 mg/kg every 2 weeks). After the MTD was defined, 15 patients were accrued to the expansion cohort.

RESULTS

Thirty-two patients were accrued (3 were treated at 60 mg/day, 21 were treated at 80 mg/day, 6 were treated at 100 mg/day, and 2 patients never received therapy). The majority of patients had clear cell histology (87%) and 50% had received ≥2 prior lines of therapy. The MTD of buparlisib was 80 mg/day and that of bevacizumab was 10 mg/kg every 2 weeks. A total of 28 patients discontinued therapy: 17 because of disease progression, 7 because of toxicity, and 4 for other reasons. Dose-limiting toxicities included rash/pruritis, elevated lipase/amylase, anorexia, and psychiatric disorders (suicidal ideation, depression, and cognitive disturbances). Of the 30 patients who received at least 1 dose, 13% achieved a partial response (95% confidence interval, 4%-31%). Two patients harboring activating PI3KA mutations achieved 42% and 16% maximal tumor shrinkage, respectively.

CONCLUSIONS

Buparlisib at a dose of 80 mg/day with bevacizumab was found to be a tolerable regimen with preliminary activity in vascular endothelial growth factor-refractory mRCC. The benefit of this combination may be of interest for future mRCC trials, possibly in a selected patient population. Cancer 2016. © 2016 American Cancer Society.

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Low WT1 transcript levels at diagnosis predicted poor outcomes of acute myeloid leukemia patients with t(8;21) who received chemotherapy or allogeneic hematopoietic stem cell transplantation

Acute myeloid leukemia (AML) with t(8;21) is a heterogeneous disease. Identifying AML patients with t(8;21) who have a poor prognosis despite achieving remission is important for determining the best subsequen...

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A multicenter phase II study of TAS-102 monotherapy in patients with pre-treated advanced gastric cancer (EPOC1201)

Publication date: July 2016
Source:European Journal of Cancer, Volume 62
Author(s): Hideaki Bando, Toshihiko Doi, Kei Muro, Hirofumi Yasui, Tomohiro Nishina, Kensei Yamaguchi, Shunji Takahashi, Shogo Nomura, Hirofumi Kuno, Kohei Shitara, Akihiro Sato, Atsushi Ohtsu
AimAmerican phase I studies have reported that the recommended dose of TAS-102 (trifluridine/tipiracil) was 25 mg/m² twice a day (b.i.d.), although this schedule did not provide clinically relevant improvements in a phase II study of advanced gastric cancer (AGC). However, a pivotal phase III study revealed that TAS-102 at 35 mg/m² b.i.d. provided a clinically relevant improvement in overall survival (OS) among patients with metastatic colorectal cancer. Therefore, we re-evaluated the efficacy, safety, and pharmacokinetic parameters of TAS-102 at 35 mg/m² b.i.d among Japanese patients with AGC.MethodsAll patients had undergone one or two previous chemotherapy regimens that contained fluoropyrimidine, platinum agents, and taxanes or irinotecan. The primary end-point target was a disease control rate (DCR) of ≥50% after 8 weeks of the 35 mg/m² b.i.d. schedule.ResultsTwenty-nine patients were assessable after completing the 35 mg/m² b.i.d. schedule. The investigator-determined DCR was 65.5% (95% confidence interval [CI], 45.7–82.1%) and the independent central review's DCR was 51.9% (95% CI, 31.9–71.3%); both results exceeded the primary end-point target. The median progression-free survival and OS were 2.9 months (95% CI, 1.1–5.3 months) and 8.7 months (95% CI, 5.7–14.9 months), respectively. The grade III/IV adverse events included neutropenia (69.0%), leucopaenia (41.4%), anaemia (20.7%), and anorexia (10.3%). No AGC-specific toxicities were detected.ConclusionsThe 35 mg/m² b.i.d. dose of TAS-102 provided positive efficacy and an acceptable toxicity profile in patients with AGC. A randomised, double-blind, placebo-controlled, phase III study is ongoing to validate these findings.Clinical trial registration numberUMIN000007421



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Low-dose computed tomography screening for lung cancer in populations highly exposed to tobacco: A systematic methodological appraisal of published randomised controlled trials

Publication date: Available online 19 May 2016
Source:European Journal of Cancer
Author(s): Gaëlle Coureau, L. Rachid Salmi, Cécile Etard, Hélène Sancho-Garnier, Catherine Sauvaget, Simone Mathoulin-Pélissier
Low-dose computed tomography (LDCT) screening recommendations for lung cancer are contradictory. The French National Authority for Health commissioned experts to carry a systematic review on the effectiveness, acceptability and safety of lung cancer screening with LDCT in subjects highly exposed to tobacco. We used MEDLINE and Embase databases (2003–2014) and identified 83 publications representing ten randomised control trials. Control arms and methodology varied considerably, precluding a full comparison and questioning reproducibility of the findings. From five trials reporting mortality results, only the National Lung Screening Trial found a significant decrease of disease-specific and all-cause mortality with LDCT screening compared to chest X-ray screening. None of the studies provided all information needed to document the risk-benefit balance. The lack of statistical power and the methodological heterogeneity of European trials question on the possibility of obtaining valid results separately or by pooling. We conclude, in regard to the lack of strong scientific evidence, that LDCT screening should not be recommended in subjects highly exposed to tobacco.



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Germline BRCA1/2 mutation testing is indicated in every patient with epithelial ovarian cancer: A systematic review

Publication date: July 2016
Source:European Journal of Cancer, Volume 61
Author(s): Marieke Arts-de Jong, Geertruida H. de Bock, Christi J. van Asperen, Marian J.E. Mourits, Joanne A. de Hullu, C. Marleen Kets
The presence of a germline BRCA1/2 mutation improves options for tailored risk-reducing strategies and treatment in both breast and ovarian cancer patients and their relatives. Currently, referral for germline BRCA1/2 mutation testing of women with epithelial ovarian cancer (EOC) varies widely, based on different criteria, such as age of onset, family history of breast and/or ovarian cancer and histological type of EOC. The overall probability of a germline BRCA1/2 mutation in women with EOC is above 10%, and a substantial part of the germline BRCA1/2 mutation carriers is missed when applying these criteria for referral. Therefore, we strongly recommend referral of all women with EOC for genetic counselling and DNA analysis.



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Pediatric Sarcomas Are Targetable by MR-Guided High Intensity Focused Ultrasound (MR-HIFU): Anatomical Distribution and Radiological Characteristics

Background

Despite intensive therapy, children with metastatic and recurrent sarcoma or neuroblastoma have a poor prognosis. Magnetic resonance guided high intensity focused ultrasound (MR-HIFU) is a noninvasive technique allowing the delivery of targeted ultrasound energy under MR imaging guidance. MR-HIFU may be used to ablate tumors without ionizing radiation or target chemotherapy using hyperthermia. Here, we evaluated the anatomic locations of tumors to assess the technical feasibility of MR-HIFU therapy for children with solid tumors.

Procedure

Patients with sarcoma or neuroblastoma with available cross-sectional imaging were studied. Tumors were classified based on the location and surrounding structures within the ultrasound beam path as (i) not targetable, (ii) completely or partially targetable with the currently available MR-HIFU system, and (iii) potentially targetable if a respiratory motion compensation technique was used.

Results

Of the 121 patients with sarcoma and 61 patients with neuroblastoma, 64% and 25% of primary tumors were targetable at diagnosis, respectively. Less than 20% of metastases at diagnosis or relapse were targetable for both sarcoma and neuroblastoma. Most targetable lesions were located in extremities or in the pelvis. Respiratory motion compensation may increase the percentage of targetable tumors by 4% for sarcomas and 10% for neuroblastoma.

Conclusions

Many pediatric sarcomas are localized at diagnosis and are targetable by current MR-HIFU technology. Some children with neuroblastoma have bony tumors targetable by MR-HIFU at relapse, but few newly diagnosed children with neuroblastoma have tumors amenable to MR-HIFU therapy. Clinical trials of MR-HIFU should focus on patients with anatomically targetable tumors.

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The Role of Childhood Infections and Immunizations on Childhood Rhabdomyosarcoma: A Report From the Children's Oncology Group

Background

Rhabdomyosarcoma (RMS) is a rare, highly malignant tumor arising from primitive mesenchymal cells that differentiate into skeletal muscle. Relatively little is known about RMS susceptibility. Based on growing evidence regarding the role of early immunologic challenges on RMS development, we evaluated the role of infections and immunizations on this clinically significant pediatric malignancy.

Procedure

RMS cases (n = 322) were enrolled from the third trial coordinated by the Intergroup Rhabdomyosarcoma Study Group. Population-based controls (n = 322) were pair matched to cases on race, sex, and age. The following immunizations were assessed: diphtheria, pertussis, and tetanus (DPT); measles, mumps, and rubella; and oral polio vaccine. We also evaluated if immunizations were complete versus incomplete. We examined selected infections including chickenpox, mumps, pneumonia, scarlet fever, rubella, rubeola, pertussis, mononucleosis, and lung infections. Conditional logistic regression models were used to calculate an odds ratio (OR) and 95% confidence interval (CI) for each exposure, adjusted for maternal education and total annual income.

Results

Incomplete immunization schedules (OR = 5.30, 95% CI: 2.47–11.33) and incomplete DPT immunization (OR = 1.56, 95% CI: 1.06–2.29) were positively associated with childhood RMS. However, infections did not appear to be associated with childhood RMS.

Conclusions

This is the largest study of RMS to date demonstrating a possible protective effect of immunizations against the development of childhood RMS. Further studies are needed to validate our findings. Our findings add to the growing body of literature, suggesting a protective role of routine vaccinations in childhood cancer and specifically in childhood RMS.

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Early Discharge of Neutropenic Pediatric Oncology Patients Admitted With Fever

Background

Fever and neutropenia (FN) is a common complication of pediatric oncology therapy and accounts for a large number of hospital admissions. Standard therapy for FN includes hospital admission and empiric antibiotics. Strict adherence to this practice leads to prolonged hospitalizations that may be unnecessary for patients at low risk of having an underlying significant infection.

Procedure

Children admitted with FN could be discharged after a minimum of 48 hr with no further antibiotic therapy once they had been afebrile for 24 hr with negative blood cultures from initial presentation, regardless of their neutrophil count. We performed a retrospective review with regard to readmissions and subsequent documented infections in FN patients discharged with an ANC of ≤500 cells/mm³.

Results

There were 299 FN admissions in 188 patients who were discharged prior to achieving an ANC of ≥500 cells/mm³. Readmission to the hospital during the same period of neutropenia occurred in 50 cases (16.7%) with 27 infections diagnosed in 21 patients. Patients discharged with an ANC of ≤100 cells/mm³ (odds ratio 3.7) and patients with acute lymphoblastic leukemia (odds ratio 2.6) were more likely to be readmitted for fever. All patients that developed a significant infection had an ANC of ≤100 cells/mm³ at admission and discharge. In patients that developed a significant infection, only one required admission to the intensive care unit with no deaths.

Conclusions

The practice of discharging patients with persistent neutropenia who are afebrile with negative blood cultures produces acceptable rates of readmission and subsequent infection and does not lead to increased morbidity and mortality.

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A School Passport as Part of a Protocol to Assist Educational Reintegration After Medulloblastoma Treatment in Childhood

Background

Medulloblastoma is the most common malignant brain tumour in children and is treated with a combination of surgery, radiotherapy and chemotherapy. These children frequently experience long-term cognitive, social and physical sequelae, which significantly affect school reintegration.

Aim

This study aimed to explore school-return experiences to create a more structured school reintegration protocol for children postmedulloblastoma.

Methods

A cohort of nine patients who had completed treatment and for whom full neuropsychometric data were available was included in the study (median time since diagnosis 8 years). Data were collected using qualitative parental questionnaires, semistructured interviews with teachers (n = 12) and healthcare professionals (HCPs) (n = 6) involved in their school reintegration. Thematic analysis was employed. A focus group with five HCPs was then used for data validation.

Results

This study uncovered the following four main subjects: (1) Information sharing; (2) education and empowerment (of educational professionals (EP) and parents); (3) communication between parents, HCPs and EPs; and (4) long-term difficulties.

Discussion

Implementation of a standardised protocol delivered within the structure of a school passport document would aid uniform follow-up. The proposed multistage protocol includes early communication and reintegration planning followed by meetings at school re-entry. Follow-up meetings are suggested to reduce information loss and reassess the child's needs. Hospital support at school transitions, inclusion of school data in long-term clinical follow-up and long-term rehabilitation are also recommended. Each stage would be supported by school passport documentation and would facilitate school and parental empowerment, paramount to the long-term sustainability of successful schooling.

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Role of isolated limb perfusion with recombinant human tumor necrosis factor α and melphalan in locally advanced extremity soft tissue sarcoma

The management of locally advanced extremity soft tissue sarcoma of the limbs is challenging, particularly for recurrent tumors and those adjacent to neurovascular bundles and joints. Typically, the tumors are large, below the fascia, and high-grade (T2b or stage III according to the American Joint Committee on Cancer) and thus require multimodal therapy. Treatment options must be tailored to patient and tumor characteristics. Isolated limb perfusion with recombinant human tumor necrosis factor α and melphalan (TNF-ILP) adds a therapeutic option to radiation therapy (RT) and systemic chemotherapy. Although the procedure is somewhat sophisticated to learn, it is a safe method and has been used now for almost 2 decades at more than 50 centers worldwide. TNF-ILP yields a high rate of complete or nearly complete pathologic tumor remission. In combination with surgical resection of the tumor remnant after isolated limb perfusion, the limb salvage rate is close to 90%. Often, patients can be spared adjuvant RT without long-term local tumor control rates being compromised. Nevertheless, TNF-ILP has never been compared with another treatment regimen in a randomized trial. This review summarizes the mode of action and standard application of TNF-ILP and focuses on a critical discussion of the role of TNF-ILP in the multimodal treatment of locally advanced primary and recurrent extremity sarcoma. Cancer 2016. © 2016 American Cancer Society.

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Acinar cell carcinoma of the pancreas in childhood

Abstract

A 12-year-old Japanese girl with pancreatic acinar cell carcinoma is presented. She was referred to our hospital with upper abdominal pain on exercise. Computed tomography scan showed a 17 × 17 × 12 cm heterogeneous mass in the right abdominal cavity centering around the pancreatic head to the anterior pararenal space. We performed pylorus-preserving pancreatoduodenectomy, because the tumor invaded the pancreatic head. Macroscopically, the tumor was a 19 × 18 cm, encapsulated mass derived from the pancreatic head without invasion to the surrounding organs, and consisted of solid and cystic portions. Histological examination showed tumor cells proliferating in an acinar pattern and invading the duodenal muscle layer. Immunohistochemically, tumor cells were positive for α1 trypsin and α1 chymotrypsin. From these histological findings, we diagnosed the lesion as an acinar cell carcinoma of the pancreas. We report this case of childhood acinar cell carcinoma, which is extremely rare, with a review of the literature.

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Bending the Cost Curve in Childhood Cancer

Abstract

Healthcare for children with cancer costs significantly more than other children. Cost reduction efforts aimed toward relatively small populations of patients that use a disproportionate amount of care, like childhood cancer, could have a dramatic impact on healthcare spending. The aims of this review are to provide stakeholders with an overview of the drivers of financial costs of childhood cancer and to identify possible directions to curb or decrease these costs. Costs are incurred throughout the spectrum of care. Recent trends in pharmaceutical costs, evidence identifying the contribution of administration costs, and overuse of surveillance studies are described. Awareness of cost and value, i.e., the outcome achieved per dollar or burden spent, in delivery of care and research is necessary to bend the cost curve. Incorporation of these dimensions of care requires methodology development, prioritization, and ethical balance.

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WHO grade II-III astrocytomas consist of genetically distinct tumor lineages

Abstract

Recent investigation revealed genetic analysis provides important information in management of gliomas, and we previously reported grade II–III gliomas could be classified into clinically relevant subgroups based on the DNA copy number aberrations (CNAs). To develop more precise genetic subgrouping, we investigated correlation of CNAs and mutational status of the gene encoding isocitrate dehydrogenase (IDH) of those tumors. We analyzed the IDH status and CNAs of 174 adult supratentorial gliomas of astrocytic or oligodendroglial origin by PCR-based direct sequencing and comparative genomic hybridization, respectively. We analyzed the relationship between genetic subclassification and clinical features. We found the most frequent aberrations in IDH mutant tumors were the combined whole arm-loss of 1p and 19q (1p/19q codel) followed by gain on chromosome arm 7q (+7q). The gain of whole chromosome 7 (+7) and loss of 10q (-10q) were detected in IDH wild-type tumors. Kaplan-Meier estimates for progression free survival showed that the tumors with mutant IDH, -1p/19q, or +7q (in the absence of +7p) survived longer than tumors with wild-type IDH, +7, or -10q. Since tumors with +7 (IDH wild-type) showed a more aggressive clinical nature, they are probably not a subtype that developed from the slowly progressive tumors with +7q (IDH mutant). Thus, tumors with a gain on chromosome 7 (mostly astrocytic) comprise multiple lineages, and such differences in their biological nature should be taken into consideration during their clinical management.

This article is protected by copyright. All rights reserved.

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Cancers, Vol. 8, Pages 51: MLK3 Signaling in Cancer Invasion

Mixed-lineage kinase 3 (MLK3) was first cloned in 1994; however, only in the past decade has MLK3 become recognized as a player in oncogenic signaling. MLK3 is a mitogen-activated protein kinase kinase kinase (MAP3K) that mediates signals from several cell surface receptors including receptor tyrosine kinases (RTKs), chemokine receptors, and cytokine receptors. Once activated, MLK3 transduces signals to multiple downstream pathways, primarily to c-Jun terminal kinase (JNK) MAPK, as well as to extracellular-signal-regulated kinase (ERK) MAPK, P38 MAPK, and NF-κB, resulting in both transcriptional and post-translational regulation of multiple effector proteins. In several types of cancer, MLK3 signaling is implicated in promoting cell proliferation, as well as driving cell migration, invasion and metastasis.

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Identifying novel therapeutic agents using xenograft models of pediatric cancer

Abstract

In the USA, the overall cure rate for all childhood cancers is seventy percent, and in many patients that ultimately fail curative therapy, initial responses to current multimodality treatments (surgery, radiation therapy and chemotherapy) is good, with overall 5-year event-free survival approaching 80 %. However, current approaches to curative therapy result in significant morbidity and long-term sequelae, including cardiac dysfunction and cognitive impairment. Furthermore, dose-intensive chemotherapy with conventional agents has not significantly improved outcomes for patients that present with advanced or metastatic disease. Classical cytotoxic agents remain the backbone for curative therapy of both hematologic and solid tumors of childhood. While 'molecularly' targeted agents have shown some clinical activity, responses are often modest and of short duration; hence, there is a need to identify new classes of cytotoxic agent that are effective in patients at relapse and that have reduced or different toxicity profiles to normal tissues. Here we review the pediatric preclinical testing program experience of testing novel agents, and the value and limitations of preclinical xenograft models and genetically engineered mouse models for developing novel agents for treatment of childhood cancer.

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The role of the addition of ovarian suppression to tamoxifen in young women with hormone-sensitive breast cancer who remain premenopausal or regain menstruation after chemotherapy (ASTRRA): study protocol for a randomized controlled trial and progress

Abstract

Background

Ovarian function suppression (OFS) has been shown to be effective as adjuvant endocrine therapy in premenopausal women with hormone receptor-positive breast cancer. However, it is currently unclear if addition of OFS to standard tamoxifen therapy after completion of adjuvant chemotherapy results in a survival benefit. In 2008, the Korean Breast Cancer Society Study Group initiated the ASTRRA randomized phase III trial to evaluate the efficacy of OFS in addition to standard tamoxifen treatment in hormone receptor-positive breast cancer patients who remain or regain premenopausal status after chemotherapy.

Methods

Premenopausal women with estrogen receptor-positive breast cancer treated with definitive surgery were enrolled after completion of neoadjuvant or adjuvant chemotherapy. Ovarian function was assessed at the time of enrollment and every 6 months for 2 years by follicular-stimulating hormone levels and bleeding history. If ovarian function was confirmed as premenopausal status, the patient was randomized to receive 2 years of goserelin plus 5 years of tamoxifen treatment or 5 years of tamoxifen alone. The primary end point will be the comparison of the 5-year disease-free survival rates between the OFS and tamoxifen alone groups. Patient recruitment was finished on March 2014 with the inclusion of a total of 1483 patients. The interim analysis will be performed at the time of the observation of the 187th event.

Discussion

This study will provide evidence of the benefit of OFS plus tamoxifen compared with tamoxifen only in premenopausal patients with estrogen receptor-positive breast cancer treated with chemotherapy.

Trial registration

ClinicalTrials.gov Identifier NCT00912548. Registered May 31 2009. Korean Breast Cancer Society Study Group Register KBCSG005. Registered October 26 2009.

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Pretreatment neutrophil-to-lymphocyte ratio is correlated with response to neoadjuvant chemotherapy as an independent prognostic indicator in breast cancer patients: a retrospective study

Abstract

Background

A high neutrophil-to-lymphocyte ratio (NLR) may be related to increased mortality in patients with lung, colorectal, stomach, liver, and pancreatic cancer. To date, the utility of NLR to predict the response to neoadjuvant chemotherapy (NAC) has not been studied. The aim of our study was to determine whether the NLR is a predictor of response to NAC and to investigate the prognostic impact of the NLR on relapse-free survival (RFS) and breast cancer-specific survival (BCSS) in patients with breast cancer who received NAC.

Methods

We retrospectively studied patients who received NAC and subsequent surgical therapy for stage II–III invasive breast carcinoma at Sun Yat-sen Memorial Hospital between 2001 and 2010. The correlation of NLR with the pathological complete response (pCR) rate of invasive breast cancer to NAC was analyzed. Survival analysis was used to evaluate the predictive value of NLR.

Results

A total of 215 patients were eligible for analysis. The pCR rate in patients with lower pretreatment NLR (NLR < 2.06) was higher than those with higher NLR (NLR ≥ 2.06) (24.5 % vs.14.3 %, p < 0.05). Those patients with higher pretreatment NLR (NLR ≥ 2.1) had more advanced stages of cancer and higher disease-specific mortality. Through a multivariate analysis including all known predictive clinicopathologic factors, NLR ≥ 2.1 was a significant independent parameter affecting RFS (HR: 1.57, 95 % CI: 1.05-3.57, p < 0.05) and BCSS (HR: 2.21, 95 % CI: 1.01-4.39, p < 0.05). Patients with higher NLR (NLR ≥ 2.1) before treatment showed significantly lower relapse-free survival rate and breast cancer-specific survival rate than those with lower NLR (NLR <2.1) (log-rank p = 0.0242 and 0.186, respectively).

Conclusions

Pretreatment NLR < 2.06 is associated with pCR rate, suggesting that NLR may be an important factor predicting the response to NAC in breast cancer patients. NLR is an independent predictor of RFS and BCSS in breast cancer patients with NLR ≥ 2.1 who receive NAC. We suggest prospective studies to evaluate NLR as a simple prognostic test for breast cancer.

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Safety and QOL in Patients with Advanced NET in a Phase 3b Expanded Access Study of Everolimus

Abstract

Background/Aims

An open-label, multi-center, expanded access study was conducted in patients with advanced neuroendocrine tumors (NET) treated with everolimus (10 mg/day) to assess safety and health-related quality of life (HRQOL).

Methods

Of the 246 patients enrolled, 126 have pancreatic NET (pNET) and 120 have non-pNET. Patients continued treatment until disease progression, unacceptable toxicity, death, until commercial availability of everolimus, or May 2012, whichever came first. Adverse events (AEs) were analyzed according to Common Terminology Criteria version 4.0. HRQOL was assessed at baseline, for three 28-day cycles, and then at every three cycles until end of treatment (EOT) with EQ-5D, EORTC QLQ-C30, and EORTC QLQ-GINET21 instruments.

Results

The most common grade 3 or 4 AEs included hyperglycemia, infections, stomatitis, fatigue, and abdominal pain. In patients with pNET, mean (± SD) EQ VAS score remained stable at EOT (baseline, 68.8 ± 19.9 vs. EOT, 66.5 ± 20.6) without clinically significant change in QLQ-C30 global health status (change from baseline, - 3.9; n = 86). For patients with non-pNET, a reduction in EQ VAS score (63.9 ± 19.0 vs. 55.3 ± 23.0) with clinically significant changes in QLQ-C30 global health status (-13.0; n = 69) was seen by EOT. EQ-5D utility scores remained stable in patients with pNET and a moderate decrease was reported by patients with non-pNET.

Conclusions

The safety profile of everolimus was consistent with the previous studies without adversely affecting HRQOL in pNET. Lower baseline HRQOL scores and more frequent comorbidities might have contributed to the worse outcomes in non-pNET.

Trial Registration

EudraCT no. 2010-023032-17

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Platelet-derived growth factor receptor/platelet-derived growth factor (PDGFR/PDGF) system is a prognostic and treatment response biomarker with multifarious therapeutic targets in cancers

Abstract

Progress in cancer biology has led to an increasing discovery of oncogenic alterations of the platelet-derived growth factor receptors (PDGFRs) in cancers. In addition, their overexpression in numerous cancers invariably makes PDGFRs and platelet-derived growth factors (PDGFs) prognostic and treatment markers in some cancers. The oncologic alterations of the PDGFR/PDGF system affect the extracellular, transmembrane and tyrosine kinase domains as well as the juxtamembrane segment of the receptor. The receptor is also involved in fusions with intracellular proteins and receptor tyrosine kinase. These discoveries undoubtedly make the system an attractive oncologic therapeutic target. This review covers elementary biology of PDGFR/PDGF system and its role as a prognostic and treatment marker in cancers. In addition, the multifarious therapeutic targets of PDGFR/PDGF system are discussed. Great potential exists in the role of PDGFR/PDGF system as a prognostic and treatment marker and for further exploration of its multifarious therapeutic targets in safe and efficacious management of cancer treatments.

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Inflammatory biomarkers and risk of cancer in 84,000 individuals from the general population

Abstract

Inflammation and cancer are tightly linked. This study tests the hypothesis that an inflammatory score based on plasma levels of C-reactive protein (CRP) and fibrinogen and whole blood leukocyte count is associated with risk of colorectal, lung, breast, and prostate cancer. A score ranging from none through three elevated biomarkers was constructed in 84,000 individuals from the Danish general population. During a median follow-up time of 4.8 years, 4,081 incident cancers occurred. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) of incident cancer. Multifactor-adjusted HRs for colorectal cancer were 1.28 (95% CI, 1.01 to 1.62), 1.79 (95% CI, 1.41 to 2.27), and 2.18 (95% CI, 1.67 to 2.86) for individuals with elevated levels of one, two, and three inflammatory biomarkers compared to individuals with none elevated biomarkers. A similar stepwise increasing risk was observed for lung and breast cancer with HRs of 3.03 (95% CI, 2.25 to 4.08) and 1.42 (95% CI, 1.11 to 1.80) for three versus none elevated biomarkers. HRs were highest within the first years of follow-up. Absolute 5-year risk of lung cancer was 7.8 (95% CI, 6.1 to 10)% among older smokers with three elevated biomarkers compared to 3.8 (95% CI, 2.6 to 5.6)% among those with none elevated biomarkers. In conclusion, simultaneously elevated CRP, fibrinogen, and leukocyte count are associated with an increased risk of colorectal, lung, and breast cancer. Cancer as a promoter of inflammation may be more likely to account for our findings than low-grade inflammation promoting cancer development. This article is protected by copyright. All rights reserved.

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Gastrointestinal and liver disease in Adult Life After Childhood Cancer in Scandinavia: A population-based cohort study

Abstract

Survival after childhood cancer diagnosis has remarkably improved, but emerging evidence suggests that cancer-directed therapy may have adverse gastrointestinal late effects. We aimed to comprehensively assess the frequency of gastrointestinal and liver late effects among childhood cancer survivors and compare this frequency with the general population. Our population-based cohort study included all one-year survivors of childhood and adolescent cancer in Denmark, Finland, Iceland, Norway, and Sweden diagnosed from the 1940s and 1950s. Our outcomes of interest were hospitalization rates for gastrointestinal and liver disorders, which were ascertained from national patient registries. We calculated standardized hospitalization rate ratios (RR) and absolute excess rates (AER) comparing hospitalizations of any gastrointestinal or liver disease and for specific disease entities between survivors and the general population. The study included 31,132 survivors and 207,041 comparison subjects. The median follow-up in the hospital registries were 10 years (range: 0 – 42) with 23% of the survivors being followed at least to the age of 40 years. Overall, survivors had a 60% relative excess of gastrointestinal or liver diseases (RR: 1.6, 95% confidence interval (CI): 1.6 – 1.7), which corresponds to an absolute excess of 360 (95% CI: 330 – 390) hospitalizations per 100,000 person-years. Survivors of hepatic tumors, neuroblastoma, and leukemia had the highest excess of gastrointestinal and liver diseases. In addition, we observed a relative excess of several specific diseases such as esophageal stricture (RR: 13; 95% CI: 9.2 – 20) and liver cirrhosis (RR: 2.9; 95% CI: 2.0 – 4.1). Our findings provide useful information about the breadth and magnitude of late complications among childhood cancer survivors, and can be used for generating hypotheses about potential exposures related to these gastrointestinal and liver late effects. This article is protected by copyright. All rights reserved.

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Modulation of tumor eIF4E by antisense inhibition: A phase I/II translational clinical trial of ISIS 183750 – an antisense oligonucleotide against eIF4E – in combination with irinotecan in solid tumors and irinotecan-refractory colorectal cancer

Abstract

The eukaryotic translation initiation factor 4E (eIF4E) is a potent oncogene that is found to be dysregulated in 30% of human cancer, including colorectal carcinogenesis (CRC). ISIS 183750 is a second-generation antisense oligonucleotide (ASO) designed to inhibit the production of the eIF4E protein. In preclinical studies we found that EIF4e ASOs reduced expression of EIF4e mRNA and inhibited proliferation of colorectal carcinoma cells. An additive antiproliferative effect was observed in combination with irinotecan. We then performed a clinical trial evaluating this combination in patients with refractory cancer. No dose limiting toxicities were seen but based on pharmacokinetic data and tolerability the dose of irinotecan was reduced to 160mg/m²-biweekly. Efficacy was evaluated in 15 patients with irinotecan-refractory colorectal cancer. The median time of disease control of 22.1 weeks. After ISIS 183750 treatment, peripheral blood levels of eIF4E mRNA were decreased in 13/19 pts. Matched pre- and post-treatment tumor biopsies showed decreased eIF4E mRNA levels in 5/9 pts. In tumor tissue, the intracellular and stromal presence of ISIS 183750 was detected by IHC in all biopsied patients. Although there were no objective responses stable disease was seen in 7/15 (47%) patients who were progressing prior to study entry, six of whom were stable at the time of the week 16 CT scan. We were also able to confirm through mandatory pre- and post-therapy tumor biopsies penetration of the ASO into the site of metastasis. This article is protected by copyright. All rights reserved.

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Clinicopathogenomic analysis of mismatch repair proficient colorectal adenocarcinoma uncovers novel prognostic subgroups with differing patterns of genetic evolution

Abstract

Cancer somatic genetic evolution is a direct contributor to heterogeneity at the clonal and molecular level in colorectal adenocarcinoma (COAD). We sought to determine the extent to which genetic evolution may be detected in COAD in routinely obtained single clinical specimens and establish clinical significance with regard to clinicopathologic and outcome data. 123 cases of routinely collected mismatch repair proficient COAD was sequenced on the Illumina Truseq Amplicon assay. Measures of intratumoral heterogeneity were assessed and the preferential timing of mutational events was assessed and compared to clinicopathologic data. Survival subanalysis was performed on 55 cases. Patient age (p=0.013) and specimen percent tumor (p=0.033) was associated with clonal diversity, and biopsy (p=0.044) and metastasis (p=0.044) returned fewer mutations per case. APC and TP53 mutations preferentially occurred early while alterations in FBXW7, FLT3, SMAD4, GNAS, and PTEN preferentially occurred as late events. Temporal heterogeneity was evident in KRAS and PIK3CA mutations. Hierarchical clustering revealed a TP53 mutant subtype and a MAPK-PIK3CA subtype with differing patterns of late mutational events. Survival subanalysis showed a decreased median progression free survival for the MAPK-PIK3CA subtype (8 months vs. 13 months; univariate logrank p=0.0380, cox model p= 0.018). Neoadjuvant therapy associated mutations were found for ERBB2 (p=0.0481) and FBXW7 (p=0.015). Our data indicate novel molecular subtypes of mismatch repair proficient COAD display differing patterns of genetic evolution which correlate with clinical outcomes. Furthermore, we report treatment acquired and/or selected mutations in ERBB2 and FBXW7. This article is protected by copyright. All rights reserved.

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Knockdown of COUP-TFII inhibits cell proliferation and induces apoptosis through upregulating BRCA1 in renal cell carcinoma cells

Abstract

COUP-TFII belongs to the nuclear receptor family, which is highly expressed in many kinds of tumors. Previous studies have shown that COUP-TFII can promote tumor progression through regulating tumor angiogenesis and cell proliferation and migration of certain cancer cells. However, the function of COUP-TFII in renal cell carcinoma (RCC) is not clear. Here we showed that clinical RCC tumor tissues showed much higher COUP-TFII expression level than adjacent normal tissues. When COUP-TFII was knocked down in RCC 769-P and 786-O cells by siRNA or shRNA-expressing lentivirus, the cell proliferation was markedly inhibited, and apoptosis increased. Moreover, the tumor growth of COUP-TFII knockdown 769-P and 786-O xenografts in nude mice was also obviously inhibited. By using RT-PCR and Western blot, we showed that the expression of the tumor suppressor gene BRCA1 was upregulated in COUP-TFII knockdown cells. Simultaneously knockdown of BRCA1 and COUP-TFII partially rescued the inhibited cell proliferation and increased apoptosis in COUP-TFII single knockdown cells. These results indicate that COUP-TFII may play an oncogenic role in RCC, and COUP-TFII may promote tumor progression through inhibiting BRCA1. This article is protected by copyright. All rights reserved.

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Integrative functional genomic delineation of the cascades of transcriptional changes involved in hepatocellular carcinoma progression

Abstract

Development of targeted therapeutics is still at its early stage for hepatocellular carcinoma (HCC) due to the incomplete understanding of the confounding regulations at signaling pathway level. In this investigation, gene co-expression based networking and integrative functional genomic modeling of HCC mRNA profiles as signaling processes were employed to understand the complex signaling cascades involved in HCC development towards understanding the avenues for targeted therapeutics. Multiple sets of genes and molecular biological processes involved during HCC development were identified from this integrative analysis: i) Loss of liver cellular features due to the reduced HNF4A & PPAR signaling in the early stages of HCC, ii) activated inflammatory and stress signals in the cirrhosis stages, and iii) highly activated cellular proliferation with the activated E2F-MYC oncogenic signaling with the gain of embryonic liver stem cell-like features in the advanced stage tumors. Upon connecting these gene-sets with the established drug sensitivity related gene signatures, targeted therapeutic strategies for the heterogeneous HCC conditions have been identified. PPAR agonist class of drugs for early stage HCC conditions, anti-inflammatory drugs for cirrhosis, and topoisomerase inhibitors for the advanced HCC conditions were inferred. Integrative functional genomic analysis of HCC transcriptome profiles at the context of signaling pathways has defined the key molecular processes involved in HCC development. Further, the study highlights the stage specific and pathway focused targeted therapeutics for HCC. These findings deserve extensive pre-clinical explorations towards the establishment of targeted therapeutics. This article is protected by copyright. All rights reserved.

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Risk of extracolonic cancers for people with biallelic and monoallelic mutations in MUTYH

Abstract

Germline mutations in the DNA base excision repair gene MUTYH are known to increase a carrier's risk of colorectal cancer. However, the risks of other (extracolonic) cancers for MUTYH mutation carriers are not well defined. We identified 266 probands (91% Caucasians) with a MUTYH mutation (41 biallelic and 225 monoallelic) from the Colon Cancer Family Registry. Mutation status, sex, age, and histories of cancer from their 1,903 first- and 3,255 second-degree relatives, were analysed using modified segregation analysis conditioned on the ascertainment criteria. Compared with incidences for the general population, HRs (95% confidence intervals [CIs]) for biallelic MUTYH mutation carriers were: urinary bladder cancer, 19(3.7–97); and ovarian cancer, 17(2.4–115). The HRs (95%CI) for monoallelic MUTYH mutation carriers were: gastric cancer, 9.3(6.7–13); hepatobiliary cancer, 4.5(2.7–7.5); endometrial cancer, 2.1(1.1–3.9); and breast cancer, 1.4(1.0–2.0). There was no evidence for an increased risk of cancers at the other sites examined (brain, pancreas, kidney or prostate). Based on the USA population incidences, the estimated cumulative risks (95%CI) to age 70 years for biallelic mutation carriers were: bladder cancer, 25%(5%–77%) for males and 8%(2%–33%) for females; and ovarian cancer, 14%(2%–65%). The cumulative risks (95%CI) for monoallelic mutation carriers were: gastric cancer, 5%(4%–7%) for males and 2.3%(1.7%–3.3%) for females; hepatobiliary cancer, 3%(2%–5%) for males and 1.4%(0.8%–2.3%) for females; endometrial cancer, 3%(2%–6%); and breast cancer 11%(8%–16%). These unbiased estimates of both relative and absolute risks of extracolonic cancers for people, mostly Caucasians, with MUTYH mutations will be important for the clinical management. This article is protected by copyright. All rights reserved.

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Preoperative chemoradiation with paclitaxel-carboplatin or with fluorouracil-oxaliplatin—folinic acid (FOLFOX) for resectable esophageal and junctional cancer: the PROTECT-1402, randomized phase 2 trial

Abstract

Background

Often curative treatment for locally advanced resectable esophageal or gastro-esophageal junctional cancer consists of concurrent neoadjuvant radiotherapy and chemotherapy followed by surgery. Currently, one of the most commonly used chemotherapy regimens in this setting is a combination of a fluoropyrimidin and of a platinum analogue. Due to the promising results of the recent CROSS trial, another regimen combining paclitaxel and carboplatin is also widely used by European and American centers. No clinical study has shown the superiority of one treatment over the other. The objective of this Phase II study is to clarify clinical practice by comparing these two chemotherapy treatments. Our aim is to evaluate, in operable esophageal and gastro-esophageal junctional cancer, the complete resection rate and severe postoperative morbidity rate associated with these two neoadjuvant chemotherapeutic regimens (carboplatin-paclitaxel or fluorouracil-oxaliplatin-folinic acid) when each is combined with the radiation regime utilized in the CROSS trial.

Methods/design

PROTECT is a prospective, randomized, multicenter, open arms, phase II trial. Eligible patients will have a histologically confirmed adenocarcinoma or squamous cell carcinoma and be treated with neoadjuvant radiochemotherapy followed by surgery for stage IIB or stage III resectable esophageal cancer. A total of 106 patients will be randomized to receive either 3 cycles of FOLFOX combined to concurrent radiotherapy (41.4 Grays) or carboplatin and paclitaxel with the same radiation regimen, using a 1:1 allocation ratio.

Discussion

This ongoing trial offers the unique opportunity to compare two standards of chemotherapy delivered with a common regimen of preoperative radiation, in the setting of operable locally advanced esophageal or gastro-esophageal junctional tumors.

Trial registration

NCT02359968 (ClinicalTrials.gov) (registration date: 9 FEB 2015), EudraCT: 2014-000649-62 (registration date: 10 FEB 2014)

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