Interventions to improve thyroid cancer survivors’ quality of life

Future Oncology Ahead of Print.


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Corrigendum

Future Oncology Ahead of Print.


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Selumetinib for the treatment of metastatic uveal melanoma: past and future perspectives

Future Oncology Ahead of Print.


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Noninvasive strategies for breast cancer early detection

Future Oncology Ahead of Print.


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The development and use of the E75 (HER2 369–377) peptide vaccine

Future Oncology Ahead of Print.


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Prognostic significance of DSG3 in rectal adenocarcinoma treated with preoperative chemoradiotherapy

Future Oncology Ahead of Print.


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Expression of miRNA-26b in the diagnosis and prognosis of patients with non-small-cell lung cancer

Future Oncology Ahead of Print.


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Cancer tolerance, resistance, pathogenicity and virulence: deconstructing the disease state

Future Oncology Ahead of Print.


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Prostate cancer glands with cribriform architecture and with glomeruloid features should be considered as Gleason pattern 4 and not pattern 3

Future Oncology Ahead of Print.


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3D tissue-engineered bone marrow: what does this mean for the treatment of multiple myeloma?

Future Oncology Ahead of Print.


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Social media in cancer care: highlights, challenges & opportunities

Future Oncology Ahead of Print.


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Key considerations in the treatment of Von Hippel-Lindau disease

Future Oncology Ahead of Print.


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Ethanol Extract of Cirsium japonicum var. ussuriense Kitamura Exhibits the Activation of Nuclear Factor Erythroid 2-Related Factor 2-dependent Antioxidant Response Element and Protects Human Keratinocyte HaCaT Cells Against Oxidative DNA Damage.

Ethanol Extract of Cirsium japonicum var. ussuriense Kitamura Exhibits the Activation of Nuclear Factor Erythroid 2-Related Factor 2-dependent Antioxidant Response Element and Protects Human Keratinocyte HaCaT Cells Against Oxidative DNA Damage.

J Cancer Prev. 2016 Mar;21(1):66-72

Authors: Yoo OK, Choi BY, Park JO, Lee JW, Park BK, Joo CG, Heo HJ, Keum YS

Abstract
Keratinocytes are constantly exposed to extracellular insults, such as ultraviolet B, toxic chemicals and mechanical stress, all of which can facilitate the aging of keratinocytes via the generation of intracellular reactive oxygen species (ROS). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that plays a critical role in protecting keratinocytes against oxidants and xenobiotics by binding to the antioxidant response element (ARE), a cis-acting element existing in the promoter of most phase II cytoprotective genes. In the present study, we have attempted to find novel ethanol extract(s) of indigenous plants of Jeju island, Korea that can activate the Nrf2/ARE-dependent gene expression in human keratinocyte HaCaT cells. As a result, we identified that ethanol extract of Cirsium japonicum var. ussuriense Kitamura (ECJUK) elicited strong stimulatory effect on the ARE-dependent gene expression. Supporting this observation, we found that ECJUK induced the expression of Nrf2, hemoxygenase-1, and NAD(P)H:quinone oxidoreductase-1 and this event was correlated with Akt1 phosphorylation. We also found that ECJUK increased the intracellular reduced glutathione level and suppressed 12-O-tetradecanoylphorbol acetate-induced 8-hydroxyguanosine formation without affecting the overall viability. Collectively, our results provide evidence that ECJUK can protect against oxidative stress-mediated damages through the activation of Nrf2/ARE-dependent phase II cytoprotective gene expression.

PMID: 27051652 [PubMed - as supplied by publisher]

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Comparison of Gastric Microbiota Between Gastric Juice and Mucosa by Next Generation Sequencing Method.

Comparison of Gastric Microbiota Between Gastric Juice and Mucosa by Next Generation Sequencing Method.

J Cancer Prev. 2016 Mar;21(1):60-65

Authors: Sung J, Kim N, Kim J, Jo HJ, Park JH, Nam RH, Seok YJ, Kim YR, Lee DH, Jung HC

Abstract
BACKGROUND: Not much is known about the role of gastric microbiota except for Helicobacter pylori in human health and disease. In this study, we aimed to detect human gastric microbiota in both gastric mucosa and gastric juice by barcoded 454-pyrosequencing of the 16S rRNA gene and to compare the results from mucosa and juice.
METHODS: Gastric biopsies and stomach juices were collected from 4 subjects who underwent standard endoscopy at Seoul National University Bundang Hospital. Gastric microbiota of antral mucosa, corpus mucosa samples, and gastric fluids were analyzed by barcoded 454-pyrosequencing of the 16S rRNA gene. The analysis focused on bacteria, such as H. pylori and nitrosating or nitrate-reducing bacteria.
RESULTS: Gastric fluid samples showed higher diversity compared to that of gastric mucosa samples. The mean of operational taxonomic units was higher in gastric fluid than in gastric mucosa. The samples of gastric fluid and gastric mucosa showed different composition of phyla. The composition of H. pylori and Proteobacteria was higher in mucosa samples compared to gastric fluid samples (H. pylori, 66.5% vs. 3.3%, P = 0.033; Proteobacteria, 75.4% vs. 26.3%, P = 0.041), while Actinobacteria, Bacteroidetes, and Firmicutes were proportioned relatively less in mucosa samples than gastric fluid. However there was no significant difference. (Actinobacteria, 3.5% vs. 20.2%, P = 0.312; Bacteroidetes, 6.0% vs. 14.8%, P = 0.329; Firmicutes, 12.8% vs. 33.4%, P = 0.246).
CONCLUSIONS: Even though these samples were small, gastric mucosa could be more effective than gastric fluid in the detection of meaningful gastric microbiota by pyrosequencing.

PMID: 27051651 [PubMed - as supplied by publisher]

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Epidemiology of Oral Lichen Planus in a Cohort of South Indian Population: A Retrospective Study.

Epidemiology of Oral Lichen Planus in a Cohort of South Indian Population: A Retrospective Study.

J Cancer Prev. 2016 Mar;21(1):55-59

Authors: Varghese SS, George GB, Sarojini SB, Vinod S, Mathew P, Mathew DG, Sebastian J, George A

Abstract
BACKGROUND: Oral lichen planus (OLP) is an immune-mediated potentially malignant disorder of the oral cavity. Dysplastic OLP has an altered cytogenic profile and can progress into oral squamous cell carcinoma. The epidemiology of OLP is well-described in several relatively large series from various geographic locations, whereas such series from southern India is rare. The aim of the present study was to determine the epidemiology of OLP in a cohort of South Indian population.
METHODS: All the case data records of 29,606 patients who visited Mar Baselios Dental College and Hospital, Kerala, India from 2014 to 2015 were retrospectively reviewed. For data review, 122 patients of OLP were selected Estimated were type, number, and location of lesions, clinical manifestation, age of the patient, gender, onset and duration of lesion, stressful life style, habits, skin involvement and associated systemic illness, and presence/absence of dysplasia.
RESULTS: When the distribution of OLP among the gender was considered, we found more prevalence in females than males. Fifty-seven percent of patients were associated with stressful lifestyle. Reticular lichen planus was the most common clinical subtype found. Bilateral buccal mucosal was the common site, when the distribution of sites of OLP were compared (P < 0.05). Hypersensitivity reaction was frequently associated with systemic illness with OLP (P < 0.05). Anaplasia was found among 5% of lichen planus lesions.
CONCLUSIONS: OLP patients had high incidence of hypersensitivity reactions and 5% of OLP lesions showed anaplasia. Long term follow-up is necessary to monitor the recurrence, prognosis, and malignant transformation of OLP.

PMID: 27051650 [PubMed - as supplied by publisher]

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Anti-inflammatory and Anti-tumorigenic Effects of Açai Berry in Helicobacter felis-infected mice.

Anti-inflammatory and Anti-tumorigenic Effects of Açai Berry in Helicobacter felis-infected mice.

J Cancer Prev. 2016 Mar;21(1):48-54

Authors: Lee JY, Kim N, Choi YJ, Nam RH, Lee S, Ham MH, Suh JH, Choi YJ, Lee HS, Lee DH

Abstract
BACKGROUND: The aim of this study was to evaluate the anti-inflammatory and anti-tumorigenic effect of açai berry after chronic Helicobacter felis colonization in the stomachs of C57BL/6 mice.
METHODS: A total of 57 four-week-old female C57BL/6 mice (18 control mice and 39 experimental mice) were used. The mice were administered orogastrically with vehicle only or vehicle containing H. felis, 5 times every other day. After inoculation of H. felis, mice were fed either a standard or an açai-containing diet and then sacrificed at 4, 24, and 52 weeks. The infection status and degree of inflammation were determined by culture and histopathology. The level of gastric mucosal myeloperoxidase (MPO), TNF-α, and interleukin-1β (IL-1β) were measured by ELISA.
RESULTS: At 24 weeks after inoculation, mucosal atrophy and mucous metaplasia appeared in all infected mice. At 52 weeks after inoculation, dysplastic change was noted in 10%, 25%, and 50% of mice in the H. felis-control, H. felis-açai 5%, and H. felis-açai 10% groups, respectively. The neutrophil, monocyte, atrophy, and metaplasia grades of infected mice showed no significant difference among the H. felis-infected groups. H. felis-infected mice fed with açai berry showed no significant difference compared with H. felis-infected control mice in gastric mucosal MPO, TNF-α, and IL-1β levels.
CONCLUSIONS: H. felis that colonized the stomachs of C57BL/6 mice provoked inflammation, and induced mucosal atrophy, metaplasia, and dysplasia. However, açai berry did not effectively prohibit the gastric carcinogenesis which was induced by chronic H. felis infection.

PMID: 27051649 [PubMed - as supplied by publisher]

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Hyperoside Induces Endogenous Antioxidant System to Alleviate Oxidative Stress.

Hyperoside Induces Endogenous Antioxidant System to Alleviate Oxidative Stress.

J Cancer Prev. 2016 Mar;21(1):41-47

Authors: Park JY, Han X, Piao MJ, Oh MC, Fernando PM, Kang KA, Ryu YS, Jung U, Kim IG, Hyun JW

Abstract
BACKGROUND: Hyperoside, a flavonoid which is mainly found in Hypericum perforatum L., has many biological effects. One of the most important effects is to prevent the oxidative stress induced by reactive oxygen species. However, the molecular mechanisms underlying its effect are not fully understood. Oxidative stress is implicated in the occurrence of various physical diseases. A wide array of enzymatic antioxidant defense systems include NADH: quinone oxidoreductase 1, superoxide dismutase, and heme oxygenase-1 (HO-1). In the present study, the protective effects of hyperoside against hydrogen peroxide-induced oxidative stress in human lens epithelial cells, HLE-B3, were investigated in terms of HO-1 induction.
METHODS: The protein and mRNA expressions of HO-1 were examined by Western blotting and reverse transcriptase-PCR assays, respectively. To evaluate the ability of hyperoside to activate nuclear factor erythroid 2-related factor 2 (Nrf2), Western blotting and electrophoretic mobility shift assay were performed with nuclear extracts prepared from HLE-B3 cells treated with hyperoside. The activation of extracellular signal-regulated kinase (ERK), the upstream kinase of Nrf2 signaling, was monitored by Western blot analysis. The protective effect of hyperoside in HLE-B3 cells against hydrogen peroxide was performed by MTT assay.
RESULTS: Hyperoside increased both the mRNA and protein expression of HO-1 in a time- and dose-dependent manner. In addition, hyperoside elevated the level of of Nrf2 and its antioxidant response element-binding activity, which was modulated by upstream of ERK. Moreover, it activated ERK and restored cell viability which was decreased by hydrogen peroxide.
CONCLUSIONS: Hyperoside is an effective compound to protect cells against oxidative stress via HO-1 induction.

PMID: 27051648 [PubMed - as supplied by publisher]

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Malvidin Protects WI-38 Human Fibroblast Cells Against Stress-induced Premature Senescence.

Malvidin Protects WI-38 Human Fibroblast Cells Against Stress-induced Premature Senescence.

J Cancer Prev. 2016 Mar;21(1):32-40

Authors: Seo HR, Choi MJ, Choi JM, Ko JC, Ko JY, Cho EJ

Abstract
BACKGROUND: Malvidin is one of the most abundant components in red wines and black rice. The effects of malvidin on aging and lifespan under oxidative stress have not been fully understood. This study focused on the anti-aging effect of malvidin on stress-induced premature senescence (SIPS) in WI-38 human lung-derived diploid fibroblasts.
METHODS: In order to determine the viability of WI-38 cells, MTT assay was conducted, and malondialdehyde level was determined using thiobarbituric acid-reactive substance assay. Protein expression of inflammation-related factors was also evaluated by Western blot analysis.
RESULTS: Acute and chronic oxidative stress via hydrogen peroxide (H2O2) treatment led to SIPS in WI-38 cells, which showed decreased cell viability, increased lipid peroxidation, and a shortened lifespan in comparison with non-H2O2-treated WI-38 cells. However, malvidin treatment significantly attenuated H2O2-induced oxidative stress by inhibiting lipid peroxidation and increasing cell viability. Furthermore, the lifespan of WI-38 cells was prolonged by malvidin treatment. In addition, malvidin downregulated the expression of oxidative stress-related proteins, including NF-κB, COX-2, and inducible nitric oxide synthase. Furthermore, protein expression levels of p53, p21, and Bax were also regulated by malvidin treatment in WI-38 cells undergoing SIPS.
CONCLUSIONS: Malvidin may potentially inhibit the aging process by controlling oxidative stress.

PMID: 27051647 [PubMed - as supplied by publisher]

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Dehydroglyasperin D Inhibits the Proliferation of HT-29 Human Colorectal Cancer Cells Through Direct Interaction With Phosphatidylinositol 3-kinase.

Dehydroglyasperin D Inhibits the Proliferation of HT-29 Human Colorectal Cancer Cells Through Direct Interaction With Phosphatidylinositol 3-kinase.

J Cancer Prev. 2016 Mar;21(1):26-31

Authors: Jung SK, Jeong CH

Abstract
BACKGROUND: Despite recent advances in therapy, colorectal cancer still has a grim prognosis. Although licorice has been used in East Asian traditional medicine, the molecular properties of its constituents including dehydroglyasperin D (DHGA-D) remain unknown. We sought to evaluate the inhibitory effect of DHGA-D on colorectal cancer cell proliferation and identify the primary signaling molecule targeted by DHGA-D.
METHODS: We evaluated anchorage-dependent and -independent cell growth in HT-29 human colorectal adenocarcinoma cells. The target protein of DHGA-D was identified by Western blot analysis with a specific antibody, and direct interaction between DHGA-D and the target protein was confirmed by kinase and pull-down assays. Cell cycle analysis by flow cytometry and further Western blot analysis was performed to identify the signaling pathway involved.
RESULTS: DHGA-D significantly suppressed anchorage-dependent and -independent HT-29 colorectal cancer cell proliferation. DHGA-D directly suppressed phosphatidylinositol 3-kinase (PI3K) activity and subsequent Akt phosphorylation and bound to the p110 subunit of PI3K. DHGA-D also significantly induced G1 cell cycle arrest, together with the suppression of glycogen synthase kinase 3β and retinoblastoma phosphorylation and cyclin D1 expression.
CONCLUSIONS: DHGA-D has potent anticancer activity and targets PI3K in human colorectal adenocarcinoma HT-29 cells. To our knowledge, this is the first report to detail the molecular basis of DHGA-D in suppressing colorectal cancer cell growth.

PMID: 27051646 [PubMed - as supplied by publisher]

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Implications of Graphic Cigarette Warning Labels on Smoking Behavior: An International Perspective.

Implications of Graphic Cigarette Warning Labels on Smoking Behavior: An International Perspective.

J Cancer Prev. 2016 Mar;21(1):21-25

Authors: Jung M

Abstract
Graphic warning labels (GWLs) have been developed as a representative non-price policy to block such marketing. This study investigated the current state and effect of the global introduction of GWLs and examines the future tasks related to GWLs. We systematically reviewed literatures on GWL and a tobacco control strategy in the past fifteen years. The policy of enforcing GWLs has spread globally based on the Framework Convention on Tobacco Control. GWLs are more effective than text warnings and are implemented in over 70 countries. The policy has showed the impact of GWLs as a preventive effect on adolescents' smoking, inducement of smoking cessation, reduction in the amount of tobacco smoked, and reduction in smoking rates. The success of an anti-smoking policy can manifests itself as an effect of individual policies, the rise of tobacco prices, and the introduction of GWLs.

PMID: 27051645 [PubMed - as supplied by publisher]

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Downregulation of Reactive Oxygen Species in Apoptosis.

Downregulation of Reactive Oxygen Species in Apoptosis.

J Cancer Prev. 2016 Mar;21(1):13-20

Authors: Jeong CH, Joo SH

Abstract
Generation of reactive oxygen species (ROS) by diverse anti-cancer drugs or phytochemicals has been closely related with the induction of apoptosis in cancers. Also, the downregulation of ROS by these chemicals has been found to block initiation of carcinogenesis. Therefore, modulation of ROS by phytochemicals emerges as a crucial mechanism to regulate apoptosis in cancer prevention or therapy. This review summarizes the current understanding of the selected chemical compounds and related cellular components that modulate ROS during apoptotic process. Metformin, quercetin, curcumin, vitamin C, and other compounds have been shown to downregulate ROS in the cellular apoptotic process, and some of them even induce apoptosis in cancer cells. The cellular components mediating the downregulation of ROS include nuclear factor erythroid 2-related factor 2 antioxidant signaling pathway, thioredoxin, catalase, glutathione, heme oxygenase-1, and uncoupling proteins. The present review provides information on the relationship between these compounds and the cellular components in modulating ROS in apoptotic cancer cells.

PMID: 27051644 [PubMed - as supplied by publisher]

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The Potential Role of Nitric Oxide in Halting Cancer Progression Through Chemoprevention.

The Potential Role of Nitric Oxide in Halting Cancer Progression Through Chemoprevention.

J Cancer Prev. 2016 Mar;21(1):1-12

Authors: Vahora H, Khan MA, Alalami U, Hussain A

Abstract
Nitric oxide (NO) in general plays a beneficial physiological role as a vasorelaxant and the role of NO is decided by its concentration present in physiological environments. NO either facilitates cancer-promoting characters or act as an anti-cancer agent. The dilemma in this regard still remains unanswered. This review summarizes the recent information on NO and its role in carcinogenesis and tumor progression, as well as dietary chemopreventive agents which have NO-modulating properties with safe cytotoxic profile. Understanding the molecular mechanisms and cross-talk modulating NO effect by these chemopreventive agents can allow us to develop better therapeutic strategies for cancer treatment.

PMID: 27051643 [PubMed - as supplied by publisher]

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Integrated Palliative Care and Oncologic Care in Non-Small-Cell Lung Cancer

Opinion statement

Palliative care integrated into standard medical oncologic care will transform the way we approach and practice oncologic care. Integration of appropriate components of palliative care into oncologic treatment using a pathway-based approach will be described in this review. Care pathways build on disease status (early, locally advanced, advanced) as well as patient and family needs. This allows for an individualized approach to care and is the best means for proactive screening, assessment, and intervention, to ensure that all palliative care needs are met throughout the continuum of care. Components of palliative care that will be discussed include assessment of physical symptoms, psychosocial distress, and spiritual distress. Specific components of these should be integrated based on disease trajectory, as well as clinical assessment. Palliative care should also include family and caregiver education, training, and support, from diagnosis through survivorship and end of life. Effective integration of palliative care interventions have the potential to impact quality of life and longevity for patients, as well as improve caregiver outcomes.

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Options in Prophylactic Surgery to Prevent Ovarian Cancer in High-Risk Women: How New Hypotheses of Fallopian Tube Origin Influence Recommendations

Opinion statement

In women at increased risk of developing ovarian cancer, risk-reducing salpingo-oophorectomy is the only intervention that has been shown to decrease mortality from ovarian cancer and is the standard of care for risk reduction. Prophylactic salpingectomy with delayed oophorectomy should be considered in high-risk premenopausal women in the setting of a clinical trial.

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Watch and Wait: Is Surgery Always Necessary for Rectal Cancer?

Opinion statement

Despite decades of high-quality research, the treatment of rectal cancer remains a work in progress. The interplay between chemotherapy, radiotherapy, and surgery is under constant rearrangement and refinement. Through this all, the desire to preserve the anal sphincters and quality of life remains at the forefront. In the past decade, standard of care for stage II or III rectal cancers in the USA has been neoadjuvant chemoradiation therapy (CRT) followed by radical surgical resection of the rectum. While timing and sequence of the CRT continues to evolve, surgical resection has remained essential in treatment. This stands in contrast to anal cancer, where surgery is reserved purely for salvage. This article describes a treatment strategy that attempts to treat rectal adenocarcinoma with CRT alone, reserving surgery for failure or salvage. Of the studies performed to date, a number are methodologically sound and show promise. However, the body of evidence has yet to reach a size to sway practitioners from the established trinity of chemotherapy, radiotherapy, and surgery. Interestingly, few trials administer post treatment full-dose systemic chemotherapy, which is the standard of care in patients undergoing surgical resection. Better identification of patients that will have complete cure from this approach, combined with long-term outcome data on salvage patients, is necessary for this therapy to be universally embraced.

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PET-CT in Staging, Response Evaluation, and Surveillance of Lymphoma

Opinion statement

Lymphoma represents a broad spectrum of diseases with diverse biology, clinical behavior, and imaging features. Functional imaging with 18-F-fluorodeoxyglucose (FDG)-positron emission tomography combined with computed tomography (PET-CT) is widely recognized as the most sensitive and specific imaging modality for patients with lymphoma and is used as part of staging, response evaluation, and surveillance in patients with Hodgkin (HL) and non-Hodgkin lymphoma (NHL). Recent efforts at standardizing the conduct and consensus interpretation of PET-CT have facilitated its use in patients on clinical studies and beyond. The role of PET-CT has been affirmed in some clinical situations, such as staging and end-of-treatment evaluation in Hodgkin lymphoma and diffuse large B cell lymphoma (DLBCL), and in the evaluation of aggressive transformation of an indolent lymphoma. However, the role of functional imaging in other histologies and clinical settings is not as clear given the higher rate of false positive results and the costs inherent to PET-CT. There is little evidence to suggest its utility or impact on outcome in most indolent lymphomas, or in the setting of post-treatment surveillance. In addition, there remains controversy about the value of PET-CT in early response assessment during active therapy, particularly in DLBCL. This review will evaluate the evidence surrounding the role of PET-CT in staging, response evaluation and surveillance of Hodgkin and non-Hodgkin lymphoma.

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Esophagogastric Adenocarcinoma: Is More Chemotherapy Better?

Opinion statement

Two cycles of neoadjuvant cisplatin and fluoropyrimidine (CF) and 6 cycles of perioperative CF with or without epirubicin are an evidence-based approach in operable esophageal and esophagogastric junctional adenocarcinomas. Three-drug regimens with anthracycline or taxane are associated with significantly higher tumor regression rates, with an expected increase in toxicity. In order to achieve an R0 resection and consequently a survival advantage, in selected patients having a risk of a threatened margin or incomplete resection, chemotherapy might be continued beyond 2 cycles if a response has been demonstrated. In metastatic setting, multidrug combination regimens have demonstrated a significant survival benefit when compared to single-agent regimes. A three-drug regimen should be considered for fit patients and/or when a response is required for symptom control. The expected increase in toxicity needs to be carefully considered and discussed with patients. The choice to use a taxane in first-line setting may limit the options of second-line treatment to irinotecan-containing regimens and also precludes the use of anthracyclines in the first line. For this reason, we prefer to reserve taxane-based therapy for the second-line setting.

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Inactivation of CYLD in intestinal epithelial cells exacerbates colitis-associated colorectal carcinogenesis - a short report

Abstract

Purpose

CYLD is a tumor suppressor that has been linked to the development of various human malignancies, including colon cancer. The tumor-suppressing function of CYLD is associated with its deubiquitinating activity, which maps to the carboxyl-terminal region of the protein. In the present study we evaluated the role of intestinal epithelial CYLD in colitis-associated cancer using a conditional mouse CYLD inactivation model.

Methods

In order to evaluate the role of CYLD in intestinal epithelial carcinogenesis, mice (IEC-Cyld ^Δ9 mice) that carry a mutation that eliminates the deubiquitinating domain of CYLD in intestinal epithelial cells (IEC) were generated by crossing Villin-Cre transgenic mice to previously generated mice carrying a loxP-flanked Cyld exon 9 (Cyld ^flx9 mice).

Results

We found that IEC-Cyld ^Δ9 mice did not present spontaneous intestinal abnormalities up to one year of age. However, upon challenge with a combination of genotoxic (AOM) and pro-inflammatory (DSS) agents we found that the number of adenomas in the IEC-Cyld ^Δ9 mice was dramatically increased compared to the control mice. Inactivation of CYLD in intestinal epithelial cells did not affect the classical nuclear factor-kappaB (NF-κB) and c-Jun kinase (JNK) activation pathways under physiological conditions, suggesting that these pathways do not predispose CYLD-deficient intestinal epithelia to colorectal cancer development before the onset of genotoxic and/or pro-inflammatory stress.

Conclusions

Our findings underscore a critical tumor-suppressing role for functional intestinal epithelial CYLD in colitis-associated carcinogenesis. CYLD expression and its associated pathways in intestinal tumors may be exploited for future prognostic and therapeutic purposes.

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TNF-α promotes breast cancer cell migration and enhances the concentration of membrane-associated proteases in lipid rafts

Abstract

Purpose

Tumor progression is associated with cell migration, invasion and metastasis. These processes are accompanied by the activation of specific proteases that are either linked to cellular membranes or are secreted into extracellular spaces. TNF-α is known to play an important role in various aspects of tumor progression. The aim of this work was to assess the effect of TNF-α on the migration of breast cancer cells and, in addition, to assess its association with the location of membrane-associated proteases in lipid rafts.

Methods

Wound scratch healing and Transwell migration assays were used to study the effect of TNF-α on the migration of both hormone-dependent and hormone-independent breast cancer-derived cells, i.e., MCF7 and MDA-MB-231, respectively. The expression and secretion of three matrix metalloproteases, MMP9, MMP2 and MT1-MMP, and two dipeptidyl peptidases, CD26 and FAP-α, was investigated using RT-PCR, Western blotting and gelatin zymography. In addition, activation of the MAPK/ERK signaling pathway was investigated by Western blotting.

Results

We found that a TNF-α-induced enhancement of breast cancer cell migration was accompanied by an increased secretion of MMP9, but not MMP2, into the culture media. We also found that TNF-α upregulated the expression of the dipeptidyl peptidases CD26 and FAP-α in a dose-dependent manner and, in addition, enhanced the concentration of all five proteases in lipid rafts in the breast cancer-derived cells tested, regardless of cell type. Furthermore, we found that TNF-α activated the MAPK/ERK signaling pathway by increasing the ERK1/2 phosphorylation level. Application of the MEK/ERK1/2 inhibitor U-0126 resulted in down-regulation of TNF-α-induced MMP9 secretion and abrogation of the enhanced concentration of proteases in the lipid rafts.

Conclusions

From our results we conclude that TNF-α-induced activation of the MAPK/ERK signaling pathway may promote breast cancer cell migration via both upregulation of MMP9, CD26 and FAP-α and concentration of these proteases, as also MT1-MMP and MMP2, in the lipid rafts. TNF-α may serve as a potential therapeutic target in breast cancers susceptible to TNF-α stimulation.

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Pharmacokinetic variations in cancer patients with liver dysfunction: applications and challenges of pharmacometabolomics

Abstract

Purpose

In cancer patients, pharmacokinetic variations between individuals and within individuals due to impairments in organs' function and other reasons such as genetic polymorphisms represent a major problem in disease management, which can result in unpredictable toxicity and variable antineoplastic effects. Addressing pharmacokinetic variations in cancer patients with liver dysfunction and their implications on anticancer and analgesic drugs, in addition to the use of advanced analytical techniques such as metabolomics and pharmacometabolomics, to monitor altered kinetic and discover metabolic biomarkers during therapeutic intervention will help in understanding and reducing pharmacokinetic variations of drugs in cancer patients as a step forward towards personalised medicine.

Methods

Reviewing published literature addressing and/or related to complications resulting from altered pharmacokinetics (PKs) in cancer patients with liver dysfunction, anticancer and analgesic drugs, evaluating recent advances of pharmacokinetic detection using metabolomics/pharmacometabolomics and the challenges that are currently facing these techniques.

Results

The current situation presents a pressing need to reduce pharmacokinetic variations of drugs in cancer patients. Although most of the omics technologies are not entirely focussed on the study of pharmacokinetic variations and some studies are met with uncertainty, the use of pharmacometabolomics combined with other omics technology such as pharmacogenomics can provide clues to personalised cancer treatments by providing useful information about the cancer patient's response to medical interventions via identification of patients' dependent variables, understanding of correlations between individuals and population PKs, and therapy outcomes to achieve optimum therapeutic effects with minimum toxicity. We also propose an approach for PKs' evaluation using pharmacometabolomics.

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A phase I dose escalation study of NK012, an SN-38 incorporating macromolecular polymeric micelle

Abstract

Purpose

This study evaluated the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) and recommended phase II dose (RD) of NK012, a macromolecular polymeric micelle formulation of SN-38 (the active metabolite of irinotecan).

Patients and methods

Patients with previously treated advanced solid tumors and acceptable organ function were administered NK012 as a 30-min infusion every 21 or 28 days without premedications. Patients were screened for UGT1A1 *28 polymorphism prior to enrollment. Patients homozygous for UGT1A1*28 allele (*28/*28 genotype patients) were treated at a reduced dose level with the potential for dose escalation based on toxicities. Pharmacokinetic samples were obtained during cycles 1 and 2.

Results

Thirty-nine patients were enrolled, and thirty-eight patients were treated with NK012. NK012 was escalated from 9 to 37 mg/m² in patients with UGT1A1*28 allele genotype of wt/wt and wt/*28. The MTD/RD of a Q21D regimen was determined to be 28 mg/m² where the dose-limiting toxicity is myelosuppression, which appears to be cumulative and limits timely subsequent dosing. Based on delayed neutrophil recovery, the NK012 dose of 28 mg/m² administered on an every 28 days schedule was confirmed as the RD. Gastrointestinal toxicities were mild, with no grade 3 diarrhea reported. The T_1/2z value of polymer-unbound SN-38 was significantly prolonged compared to that of SN-38 metabolized from CPT-11, indicating a sustained high systemic SN-38 concentration. Six patients had confirmed partial responses. Eighteen additional patients had stable disease as their best response to treatment.

Conclusions

The recommended phase II dose of NK012 for UGT1A1 wt/wt and wt/*28 genotype patients is 28 mg/m² every 28 days. Additional clinical development as a single agent in specific patient populations or in combination with other chemotherapy agents is warranted.

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Randomized phase III trial of amrubicin/cisplatin versus etoposide/cisplatin as first-line treatment for extensive small-cell lung cancer

Abstract

Background

Extensive-disease small-cell lung cancer (ED-SCLC) is characterized by rapid progression and relapse, despite high initial response rates to chemotherapy. The primary objective of this trial was to demonstrate the non-inferiority of amrubicin and cisplatin (AP) combination therapy compared with the standard first-line regimen of etoposide and cisplatin (EP) for previously untreated ED-SCLC in a Chinese population. When non-inferiority was verified, the objective was switched from non-inferiority to superiority.

Methods

From June 2008 to July 2010, 300 patients were enrolled and randomly assigned at a 1:1 ratio to AP and EP groups. AP-treated patients received cisplatin (60 mg/m², day 1) and amrubicin (40 mg/m², days 1–3) once every 21 days. EP-treated patients received cisplatin (80 mg/m², day 1) and etoposide (100 mg/m², days 1–3) once every 21 days. Treatment was continued for four to six cycles, except in cases of progressive disease or toxicity, and patient refusal.

Results

Median overall survival (OS) for AP vs. EP treatment was 11.8 vs. 10.3 months (p = 0.08), respectively, demonstrating non-inferiority of AP to EP (AP group: 95 % confidence interval for hazard ratio 0.63–1.03 months). Median progression-free survival and overall response rates for AP vs. EP groups were 6.8 vs. 5.7 months (p = 0.35) and 69.8 % vs. 57.3 %, respectively. Drug-related adverse events in both groups were similar, with neutropenia being the most frequent (AP 54.4 %; EP 44.0 %). Leukopenia, pyrexia, and fatigue were more prevalent in the AP group, but all were clinically reversible and manageable.

Conclusions

AP therapy demonstrated non-inferiority to EP therapy, prolonging OS for 1.5 months, but this difference was not statistically significant; thus we propose AP as a promising treatment option for ED-SCLC in China.

Trial registration

This trial was registered on 10 April 2008 (ClinicalTrials.gov NCT00660504).

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Lower rate-pressure product during submaximal walking: a link to fatigue improvement following a physical activity intervention among breast cancer survivors

Abstract

Purpose

Research showing a link between exercise-induced changes in aerobic fitness and reduced fatigue after a cancer diagnosis has been inconsistent. We evaluated associations of fatigue and rate-pressure product (RPP), a reliable index of myocardial oxygen demand, at rest and during submaximal walking following a physical activity intervention among post-primary treatment breast cancer survivors (BCS).

Methods

Secondary analyses of 152 BCS in a randomized controlled trial testing a physical activity intervention (INT) versus usual care (UC) were performed. The INT group completed counseling/group discussions along with supervised exercise sessions tapered to unsupervised exercise. Evaluations were made at baseline and immediately post-intervention (M3) on measures of physical activity (accelerometry), graded walk test, and average fatigue over the previous 7 days. RPP was calculated by dividing the product of heart rate and systolic blood pressure by 100.

Results

Resting and submaximal RPPs were significantly improved in both groups at M3; however, the magnitude of change (∆) was greater in the INT group from stage 1 (∆RPP1; INT −13 ± 17 vs. UC −7 ± 18; p = 0.03) through stage 4 (∆RPP4; INT −21 ± 26 vs. UC −9 ± 24; p < 0.01) of the walk test. The INT group reported significantly reduced fatigue (INT −0.7 ± 2.0 vs. UC +0.1 ± 2.0; p = 0.02) which was positively associated with ∆RPP during stages 2–4 of the walk test but not ∆aerobic fitness.

Conclusions

Lower RPP during submaximal walking was significantly associated with reduced fatigue in BCS.

Implications for Cancer Survivors

Exercise/physical activity training programs that lower the physiological strain during submaximal walking may produce the largest improvements in reported fatigue.

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Adiponectin and colorectal cancer

Abstract

Colorectal cancer is an obesity-related malignancy. Adiponectin is an adipokine produced exclusively by adipose tissue, and its concentration in the serum is reduced in obesity. A low serum level of adiponectin is associated with an increased risk of various types of malignancies including colorectal cancer. These facts suggest that the epidemiological link between obesity and cancer may have a significant association with adiponectin. Although numerous studies of colorectal cancer have been reported, the results are conflicting about the anti-cancer effect of adiponectin, and how adiponectin affects carcinogenesis or cancer development remains controversial. Because adiponectin has multiple systemic effects and exists as a high serum concentration protein, the main role of adiponectin should be regulation of homeostasis, and it would not likely act as an anti-cancerous hormone. However, as epidemiological evidence shows, a low adiponectin level may be a basic risk factor for colorectal cancer. We speculate that when the colonic epithelium is stimulated or damaged by another carcinogen under the condition of a low adiponectin level, carcinogenesis is promoted and cancer development is facilitated. In this report, we summarize recent findings of the correlation between adiponectin and colorectal cancer and investigate the effect of adiponectin on colorectal cancer.

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Outcomes of patients with loco-regionally recurrent or new primary squamous cell carcinomas of the head and neck treated with curative intent reirradiation at Mayo Clinic

We reviewed outcomes of patients with loco-regionally recurrent (LRR) or new primary (NP) squamous cell carcinoma of the head and neck (SCCHN) treated at our institution with reirradiation (RRT).

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Feasibility and Outcomes of Oncology Teaching for 5th Year Medical Students

Abstract

This study explored medical students' opinions of undergraduate oncology teaching, aiming to define optimal strategies for nonspecialist oncology teaching. A cross-sectional study was conducted at Al Imam Muhammed Ibn Saud Islamic University, Riyadh, Saudi Arabia. Between August 2014 and June 2015, 124 medical students completing the oncology course in the fifth year at the College of Medicine, Al Imam Muhammed Ibn Saud Islamic University, were given a 47-item questionnaire. One hundred and five students completed the questionnaire. Students reported that the oncology teaching fitted well with the course and that they gained knowledge and clinical skills, including understanding of how to break bad news. There was no consensus regarding whether physicians had an ongoing responsibility of care if patients were unable to embrace the treatment offered and whether pain was adequately controlled in patients with cancer. There was good understanding of the ethics of analgesia use and the need to involve patients in the decision-making process. There was a wide spread of opinion when asked if the physician should "decide for themselves how much information to give." Forty-four percent of students stated that they would attend an oncology summer school. This study shows the undergraduate oncology course to be effective in teaching knowledge, ethics, and skills and to be well received by fifth year medical students. Inclusion of appropriate teaching in medical school curricula may be the most effective way to ensure all clinicians acquire appropriate training in oncology.

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Combinations of the Variant Genotypes of CYP1A1 , GSTM1 and GSTT1 are Associated with an Increased Lung Cancer Risk in North Indian Population: a Case-Control Study

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Aberrant Expression of Calretinin, D2–40 and Mesothelin in Mucinous and Non-Mucinous Colorectal Carcinomas and Relation to Clinicopathological Features and Prognosis

Abstract

CRC is a heterogeneous disease in terms of morphology, invasive behavior, metastatic capacity, and clinical outcome. Recently, many so-called mesothelial markers, including calretinin, D2–40, WT1, thrombomodulin, mesothelin, and others, have been certified. The aim of this study was to assess the immunohistochemical expression of calretinin and other mesothelial markers (D2–40 and mesothelin) in colorectal mucinous adenocarcinoma (MA) and non mucinous adenocarcinoma (NMA) specimens and relation to clinicopathological features and prognosis using manual tissue microarray technique. We studied tumor tissue specimens from 150 patients with colorectal MA and NMA who underwent radical surgery from January 2007 to January 2012. High-density manual tissue microarrays were constructed using a modified mechanical pencil tip technique, and paraffin sections were submitted for immunohistochemistry using Calretinin, D2–40 and mesothelin expressions. We found that NMA showed significantly more calretinin and D2–40 expression than MA In contrast, no statistically significant difference between NMA and MA was detected in mesothelin expression. There were no statistically significant relations between any of the clinicopathological or histological parameters and any of the three markers. In a univariate analysis, neither calretinin nor D2–40 expressions showed any significant relations to DFS or OS. However, mesothelin luminal expression was significantly associated with worse DFS. Multivariate Cox regression analysis proved that luminal mesothelin expression was an independent negative prognostic factor in NMA. In conclusion, Calretinin, D2–40 and mesothelin are aberrantly expressed in a proportion of CRC cases with more expression in NMA than MA. Aberrant expression of these mesothelial markers was not associated with clinicopathological or histological features of CRCs. Only mesothelin expression appears to be a strong predictor of adverse prognosis.

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Age-related changes in natural killer cell repertoires: impact on NK cell function and immune surveillance

Abstract

A key feature of human natural killer (NK) cells, which enables efficient recognition of infected and malignant target cells, is the expression of HLA class I-specific receptors of the KIR and NKG2 gene families. Cell-to-cell variability in receptor expression leads to the formation of complex NK cell repertoires. As outlined here, NK cells go through major changes from newborns to adults characterized by downregulation of the inhibitory NKG2A receptor and concomitant upregulation of KIR family members. This process is completed in young adults, and in the majority of individuals, KIR/NKG2A repertoires remain remarkably stable until old age. Nonetheless, age-related factors have the potential to majorly influence the complexity of NK cell repertoires: Firstly infection with HCMV is associated with major clonal expansions of terminally differentiated NKG2C- and KIR-expressing NK cells in certain individuals. Secondly, ineffective hematopoiesis can lead to immature and less diversified NK cell repertoires as observed in myelodysplastic syndrome (MDS), a malignant disease of the elderly. Thus, whereas in the majority of elderly the NK cell compartment appears to be highly stable in terms of function and phenotype, in a minority of subjects a breakdown of NK cell repertoire diversity is observed that might influence immune surveillance and healthy aging.

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Natural killer cell immunosenescence in acute myeloid leukaemia patients: new targets for immunotherapeutic strategies?

Abstract

Several age-associated changes in natural killer (NK) cell phenotype have been reported that contribute to the defective NK cell response observed in elderly patients. A remodelling of the NK cell compartment occurs in the elderly with a reduction in the output of immature CD56^bright cells and an accumulation of highly differentiated CD56^dim NK cells. Acute myeloid leukaemia (AML) is generally a disease of older adults. NK cells in AML patients show diminished expression of several activating receptors that contribute to impaired NK cell function and, in consequence, to AML blast escape from NK cell immunosurveillance. In AML patients, phenotypic changes in NK cells have been correlated with disease progression and survival. NK cell-based immunotherapy has emerged as a possibility for the treatment of AML patients. The understanding of age-associated alterations in NK cells is therefore necessary to define adequate therapeutic strategies in older AML patients.

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Human natural killer cells: news in the therapy of solid tumors and high-risk leukemias

Abstract

It is well established that natural killer (NK) cells play an important role in the immunity against cancer, while the involvement of other recently identified, NK-related innate lymphoid cells is still poorly defined. In the haploidentical hematopoietic stem cell transplantation for the therapy of high-risk leukemias, NK cells have been shown to exert a key role in killing leukemic blasts residual after conditioning. While the clinical results in the cure of leukemias are excellent, the exploitation of NK cells in the therapy of solid tumors is still limited and unsatisfactory. In solid tumors, NK cell function may be inhibited via different mechanisms, occurring primarily at the tumor site. The cellular interactions in the tumor microenvironment involve tumor cells, stromal cells and resident or recruited leukocytes and may favor tumor evasion from the host's defenses. In this context, a number of cytokines, growth factors and enzymes synthesized by tumor cells, stromal cells, suppressive/regulatory myeloid and lymphoid cells may substantially impair the function of different tumor-reactive effector cells, including NK cells. The identification and characterization of such mechanisms may offer clues for the development of new immunotherapeutic strategies to restore effective anti-tumor responses. In order to harness NK cell-based immunotherapies, several approaches have been proposed, including reinforcement of NK cell cytotoxicity by means of specific cytokines, antibodies or drugs. These new tools may improve NK cell function and/or increase tumor susceptibility to NK-mediated killing. Hence, the integration of NK-based immunotherapies with conventional anti-tumor therapies may increase chances of successful cancer treatment.

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Mechanistic and clinical aspects of lenalidomide treatment for chronic lymphocytic leukemia.

Mechanistic and clinical aspects of lenalidomide treatment for chronic lymphocytic leukemia.

Curr Cancer Drug Targets. 2016 Apr 8;

Authors: Riches JC, Gribben JG

Abstract
There have been significant advances in our understanding of the pathogenesis of chronic lymphocytic leukemia (CLL) over the last decade, which has been accompanied by a rapid increase in treatment options. Inhibitors of BCR-signaling such as ibrutinib and idelalisib, and pro-apoptotic agents such as ABT-199 have shown great promise in initial clinical trials and have been at the forefront of recent developments. However, despite the encouraging early data, these agents do not appear to represent a "cure" for CLL and mechanisms of resistance to these agents have already been identified. In light of these considerations there remains a need for alternative treatment strategies. Lenalidomide, a second-generation derivative of thalidomide, has been demonstrated to have significant clinical activity in CLL. Its effect appears to be mediated by reduction of CLL-cell proliferation, improvement of anti-tumor immune responses and reduction of pro-tumoral factors in the CLL microenvironment. This review discusses our current understanding of the mechanism of action of lenalidomide on both healthy cells and in CLL. It also summarises the published clinical trial experience with this drug, and proposes an ongoing role for this agent in the CLL armamentarium.

PMID: 27055579 [PubMed - as supplied by publisher]

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Therapeutic Approach to Patients with Chronic Lymphocytic Leukemia and Significant Comorbid Conditions.

Therapeutic Approach to Patients with Chronic Lymphocytic Leukemia and Significant Comorbid Conditions.

Curr Cancer Drug Targets. 2016 Apr 8;

Authors: Smolej L

Abstract
Clinical trials in chronic lymphocytic leukemia (CLL) have focused mainly on younger fit patients until recently. However, CLL is a disease of elderly and many patients have significant comorbid conditions which together with advanced age preclude the use of aggressive regimens like FCR (fludarabine, cyclophosphamide, rituximab). Therefore, parameters such as performance status, renal function and number/severity of comorbidities together with clinical judgment should be used to guide the decision-making process regarding intensity of treatment. Two large randomized trials recently demonstrated that addition of monoclonal anti-CD20 antibodies (obinutuzumab, rituximab, and ofatumumab) to chlorambucil in untreated comorbid patients lead to improvement in complete remission rate, progression-free survival and even overall survival (obinutuzumab-chlorambucil and rituximab-chlorambucil), with acceptable toxicity profile. Thus, chemoimmunotherapy combining chlorambucil with an anti-CD20 antibody is the new standard approach for elderly/comorbid CLL patients in the first line. Treatment of relapsed/refractory disease in this patient population is very challenging and data regarding this subpopulation are rather limited. Impressive efficacy of novel targeted small molecules interfering with B-cell receptor signaling, namely Bruton tyrosine kinase inhibitor ibrutinib and phosphatidylinositol-3 kinase delta inhibitor idelalisib, radically changed the treatment paradigms for relapsed/refractory CLL; relatively mild toxicity of these agents make them very good candidates for elderly/comorbid patients. Other options for relapsed/refractory disease include alemtuzumab, ofatumumab, high-dose glucocorticoids+rituximab and bendamustine+rituximab. This review summarizes the current knowledge on prognostication and therapy of elderly and comorbid patients with CLL.

PMID: 27055578 [PubMed - as supplied by publisher]

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Refractory Chronic Lymphocytic Leukemia: a Therapeutic Challenge.

Refractory Chronic Lymphocytic Leukemia: a Therapeutic Challenge.

Curr Cancer Drug Targets. 2016 Apr 8;

Authors: Smolej L

Abstract
Despite impressive therapeutic progress represented by the advent of chemoimmunotherapy, chronic lymphocytic leukemia (CLL) remains incurable by conventional modalities. Refractory CLL defined by non-response to treatment or relapse/progression within 6 months is associated with multiple unfavourable prognostic factors such as p53 pathway disruption, deteriorating patient condition, increased risk of severe infections, and poor response to treatment, resulting in a very short overall survival. Therefore, refractory CLL represents a highly challenging situation for the hematologist as well as the patient. The amount and quality of data on refractory CLL are rather limited as clinical trials usually combine patients with relapsed and refractory disease. Therapeutic options for refractory CLL include alemtuzumab, ofatumumab, fludarabine- and bendamustine-based regimens, platinum-based aggressive protocols and high-dose corticosteroids combined with monoclonal antibodies. The recent introduction of ibrutinib and idelalisib, small molecules interfering with B-cell receptor pathways, revolutionized the treatment of refractory CLL by the novel concept of long-term, oral treatment leading to impressive progression-free and overall survival improvement. Allogeneic stem cell transplantation is still considered the only option with curative potential. This review focuses on the currently available therapeutic strategies for refractory CLL.

PMID: 27055577 [PubMed - as supplied by publisher]

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Updates in preserving reproductive potential of prepubertal girls with cancer: Systematic review

Publication date: Available online 8 April 2016
Source:Critical Reviews in Oncology/Hematology
Author(s): Mahmoud Salama, Vladimir Isachenko, Evgenia Isachenko, Gohar Rahimi, Peter Mallmann
IntroductionWith increasing numbers of adult female survivors of childhood cancers due to advances in early diagnosis and treatment, the issue of preserving the reproductive potential of prepubertal girls undergoing gonadotoxic treatments has gained greater attention.MethodsAccording to PRISMA guidelines, a systematic review of the literature was performed for all relevant full-text articles published in PubMed in English throughout the past 15 years to explore the significant updates in preserving the reproductive potential of prepubertal girls with cancer.ResultsThe two established fertility preservation options, embryo freezing and egg freezing, cannot be offered routinely to prepubertal girls as these options necessitate prior ovarian stimulation and subsequent mature oocytes retrieval that are contraindicated or infeasible before puberty. Therefore, the most suitable fertility preservation options to prepubertal girls are (1) ovarian tissue freezing and autotransplantation, (2) in vitro maturation, and (3) ovarian protection techniques. In this review, we discuss in detail those options as well as their success rates, advantages, disadvantages and future directions. We also suggest a new integrated strategy to preserve the reproductive potential of prepubertal girls with cancer.ConclusionAlthough experimental, ovarian tissue slow freezing and orthotopic autotransplantation may be the most feasible option to preserve the reproductive potential of prepubertal girls with cancer. However, this technique has two major and serious disadvantages: (1) the risk of reintroducing malignant cells, and (2) the relatively short lifespan of ovarian tissue transplants. Several medical and ethical considerations should be taken into account before applying this technique to prepubertal girls with cancer.



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[Chemoradiation for locally advanced head and neck cancers: Cetuximab or cisplatin?]

[Chemoradiation for locally advanced head and neck cancers: Cetuximab or cisplatin?]

Bull Cancer. 2016 Apr 4;

Authors: Mazeron JJ

PMID: 27055355 [PubMed - as supplied by publisher]

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Associations between hematopoietic growth factors and risks of venous thromboembolism, stroke, ischemic heart disease and myelodysplastic syndrome: findings from a large population-based cohort of women with breast cancer

Abstract

Purpose

To determine the risk of venous thromboembolism (VTE), stroke, ischemic heart disease, and myelodysplastic syndrome (MDS) in association with the receipt of colony-stimulating factors (CSFs) and/or erythropoiesis-stimulating agents (ESAs) in women with breast cancer.

Methods

We studied 77,233 women with breast cancer aged ≥65 in 1992–2009 from the Surveillance, Epidemiology, and End Results-Medicare linked data with up to 19 years of follow-up.

Results

Incidence of VTE increased from 9 cases in women receiving no chemotherapy and no CSFs/ESAs to 22.79 cases per 1,000 person-years in those receiving chemotherapy with CSFs and ESAs. Women with chemotherapy who received both CSFs and ESAs (adjusted hazard ratio and 95 % confidence interval 2.01, 1.80–2.25) or received ESAs without CSFs (2.03, 1.74–2.36) were twice as likely to develop VTE than those receiving no chemotherapy and no CSFs/ESAs, whereas those receiving CSF alone without ESA were 64 % more likely to have VTE (1.64, 1.45–1.85). Risk of MDS was significantly increased by fivefold in patients receiving ESA following chemotherapy.

Conclusions

Receipts of CSFs and ESAs were significantly associated with an increased risk of VTE in women with breast cancer. Use of ESAs was significantly associated with substantially increased risks of MDS. These findings support those of previous studies.

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Assessment of the antitumor potential of Bithionol in vivo using a xenograft model of ovarian cancer.

In terms of the concept of 'drug repurposing', we focused on pharmaceutical-grade Bithionol (BT) as a therapeutic agent against ovarian cancer. Our recent in-vitro study provides preclinical data suggesting a potential therapeutic role for BT against recurrent ovarian cancer. BT was shown to cause cell death by caspases-mediated apoptosis. The present preliminary study further explores the antitumor potential of pharmaceutical-grade BT in an in-vivo xenograft model of human ovarian cancer. Nude Foxn1nu mice bearing SKOV-3 human ovarian tumor xenografts were treated with titrated doses of BT and the therapeutic efficacy of pharmaceutical BT was determined using bioluminescence imaging. BT-induced changes in cell proliferation and apoptosis were evaluated by Ki-67 immunochemical staining and TUNEL assay. The effect of BT on autotaxin levels in serum, ascitic fluid, and tumor tissue was assessed by colorimetric and western blot techniques. BT treatment did not show antitumor potential or enhanced survival time at any of the doses tested. No apparent signs of toxicity were observed with any of the doses tested. Immunohistological analysis of tumor sections did not indicate a significant decrease in cellular proliferation (Ki-67 assay). An increase in apoptosis (by TUNEL assay) was observed in all BT-treated mice compared with vehicle-treated mice. Although BT did not show significant antitumor activity in the present study, the ability of BT to induce apoptosis still makes it a promising therapeutic agent. Further confirmatory and optimization studies are essential to enhance the therapeutic effects of BT. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Neoadjuvant dose-dense chemotherapy for locally advanced breast cancer: a meta-analysis of published studies.

Large operable or locally advanced breast cancers (BCs) are usually treated with neoadjuvant chemotherapy (CT) before surgery. However, there is no evidence to support an improvement in efficacy with dose-dense (DD) CT in this setting. We, therefore, carried out a meta-analysis to investigate whether DD-CT was more effective than the reference (every 3 weeks anthracyclines+/-taxanes) standard-dose CT as neoadjuvant treatment for BC. We searched Pubmed, SCOPUS, EMBASE, the Web of Science, CINAHL, and the Cochrane Central Register of Controlled Trials for randomized trials comparing conventional versus DD neoadjuvant CT for BC. Odds ratios (ORs) for pathologic complete responses (ypT0N0M0: pCR) and hazard ratios (HRs) of death and recurrence [overall survival (OS), and disease-free survival (DFS)] were estimated and pooled. A QUADAS-2 report for all studies included in the final analysis was tabulated for the risk of bias and applicability. A total of six randomized trials fulfilled the inclusion criteria. The pooled rates of the pCR were 13.5 and 9.2% in the experimental and control arms. A significant increase in the pCR [OR=1.55, 95% confidence interval (CI) 1.18-2.02, P=0.001] was noted with neoadjuvant DD-CT. However, the patients who received DD-CT did not have significantly better DFS and OS rates (DFS: HR=0.88, 95% CI 0.76-1.01, P=0.06; OS: HR=0.89, 95% CI 0.78-1.02, P=0.08). Even with the limitation of a relatively short follow-up period, this meta-analysis shows that DD neoadjuvant CT, despite not leading to a significant increase in survival, increases by 46.7% the possibility of achieving a pCR in operable and locally advanced BC. This treatment should thus be considered one of the backbone treatments of choice when neoadjuvant therapy is planned. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Effectiveness, toxicity, and economic evaluation of ipilimumab for the treatment of patients with metastatic melanoma in the Spanish outpatient setting.

To evaluate the effectiveness and toxicity profile of ipilimumab treatment and to examine the cost-effectiveness relation in a real-world sample of patients with metastasic melanoma. This was a multicenter, observational, retrospective cohorts study. To assess the effectiveness and safety of ipilimumab treatment progression-free survival (PFS), overall survival (OS) and adverse events were registered. An economic evaluation was performed and cost-effectiveness ratios (CERs) were calculated. Eleven patients were included, mean age 59 (SD=11) years. The median PFS was 3.83 months (95% confidence interval 0.98-9.80) and the median OS was 5.15 months (95% confidence interval 1.70-8.48). None of the patients included in the study achieved an objective response. A stable disease was achieved in four (36%) patients. The most commonly reported analytical adverse event was anemia, with all patients developing anemia in any grade. The most severe adverse event was neutropenia (n=6; 55%), with three patients developing grade 4 neutropenia (3/11; 27%). The total cost of ipilimumab treatment was [Euro sign]483 397, with a median of 43 033 (interquartile range=9555) euros per patient. The median-based CER was 136 675 (28 539-474 865) euros per progression-free year gained and the median-based CER was 100 112 (23 107-374 893) euros per life-year gained. PFS observed in real-world patients was higher than that reported in clinical trials and OS was lower. The incidence of adverse events was higher. The additional cost per progression-free year gained was ~[Euro sign]136 675. The data from this study fill an important need for information on the relative value of this treatment in terms of cost-effectiveness. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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I{kappa}B kinase {beta} in human prostate cancer

NF-B plays an important role in many types of cancer, including prostate cancer (PCa), but the role of the upstream kinase of NF-B, IKKβ, in PCa has not been fully documented, nor are there any effective IKKβ inhibitors used in clinical settings. Here, we have shown that IKKβ activity is mediated by multiple kinases including IKKα in human PCa cell lines that express activated IKKβ. Immunohistochemical analysis (IHC) of human PCa tissue microarrays (TMA) demonstrates that phosphorylation of IKKα/β within its activation loop gradually increases in low to higher stage tumors as compared to normal tissue. The expression of cell proliferation and survival markers (Ki67, Survivin), epithelial-to-mesenchymal transition (EMT) markers (Slug, Snail), as well as cancer stem cell (CSC) related transcription factors (Nanog, Sox2, Oct-4), also increase in parallel among the respective TMA samples analyzed. IKKβ, but not NF-B, is found to regulate Nanog, which, in turn, modulates the levels of Oct4, Sox2, Snail and Slug, indicating an essential role of IKKβ in regulating cancer stem cells and EMT. The novel IKKβ inhibitor CmpdA inhibits constitutively activated IKKβ/NF-B signaling, leading to induction of apoptosis and inhibition of proliferation, migration and stemness in these cells. CmpdA also significantly inhibits tumor growth in xenografts without causing apparent in vivo toxicity. Furthermore, CmpdA and docetaxel act synergistically to inhibit proliferation of PCa cells. These results indicate that IKKβ plays a pivotal role in PCa, and targeting IKKβ, including in combination with docetaxel, may be a potentially useful strategy for treating advanced PCa.

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TRX-E-002-1 prevents ovarian cancer recurrence

Chemoresistance is a major hurdle in the management of patients with epithelial ovarian cancer and is responsible for its high mortality. Studies have shown that chemoresistance is due to the presence of a subgroup of cancer cells with stemness properties and a high capacity for tumor repair. We have developed a library of super-benzopyran analogues to generate potent compounds that can induce cell death in the chemoresistant cancer stem cells. TRX-E-002-1 is identified as the most potent analog and can induce cell death in all chemoresistant CD44+/MyD88+ ovarian cancer stem cells tested (IC50 ~ 50 nM). TRX-E-002-1 is also potent against spheroid cultures formed from cancer stem cells, chemosensitive CD44-/MyD88- ovarian cancer cells, and heterogeneous cultures of ovarian cancer cells. Cell death was associated with the phosphorylation and increased levels of c-Jun and induction of caspases. In vivo, TRX-E-002-1 given as daily i.p. monotherapy at 100 mg/kg significantly decreased i.p. tumor burden compared to vehicle control. When given in combination with Cisplatin, animals receiving the combination of Cisplatin and TRX-E-002-1 showed decreased tumor burden compared to each monotherapy. Finally, TRX-E-002-1 given as maintenance treatment post-Paclitaxel significantly delayed disease recurrence. Our results suggest that TRX-E-002-1 may fill the current need for better therapeutic options in the control and management of recurrent ovarian cancer and may help improve patient survival.

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DDGP versus SMILE in NK/T cell Lymphoma

Purpose:Optimal treatment strategies for advanced natural killer/T (NK/T) cell lymphoma have not been fully defined. We compared the safety and efficacy of DDGP and SMILE regimens for advanced NK/T cell lymphoma in a randomized controlled, multicenter and open-label clinical trial. Experimental Design:Patients were newly diagnosed in stage III-IV and had performance scores in 0-2. Six cycles of DDGP (dexamethasone, cisplatin, gemcitabline, pegaspargase) or SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide) chemotherapy were randomly assigned to them. The primary end point was progression free survival. Secondary end points included response rate and overall survival. The trial is ongoing and is registered with ClinicalTrials.gov (No. NCT01501149). Results:Of 42 patients enrolled, 21 were treated with DDGP therapy and 21 patients were treated with SMILE therapy. The 1-year progression-free survival (PFS) and 2-year overall survival (OS) rates were better in DDGP group than that in SMILE group (86% versus 38% for 1-year PFS, P=0.006; 74% versus 45% for 2-year OS, P =0.027). Complete remission (CR) rate and overall response rate (ORR) of DDGP group were higher than that in SMILE group (71% versus 29%, P =0.005 for CR rate; 95% versus 67%, P =0.018 for ORR). SMILE group showed more serious leucopenia (P =0.030) and severe allergic reaction (P =0.015) than DDGP group. In addition, 2 cases in SMILE group underwent grade 4 mucosal reaction. Conclusions:DDGP chemotherapy resulted in significant improvement in PFS, OS and better tolerability compared with SMILE chemotherapy for newly diagnosed advanced NK/T cell lymphoma patients.

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TGF{beta}2 in breast milk exosomes

Purpose:Pregnancy increases breast cancer risk for all women for at least 5 years after parturition. During weaning and involution the breast microenvironment becomes tumor promotional. Exosomes provide cell-cell communication during physiologic processes such as lactation, but also in breast cancer. We determined if molecules in milk exosomes from healthy lactating women modulate the development and progression of breast cancer. Experimental Design:13 nursing women provided 3 (transitional, mature, and wean) milk samples. Exosomes were extracted and MCF7 and -10A breast cells labeled. The expression of 6 proteins linked to breast cancer were measured. Based on the findings, TGFβ2 concentration in exosome samples measured, breast cells incubated with the exosomes and effect (epithelial mesenchymal transition-EMT) and EMT related proteins (E-cadherin, α-smooth muscle actin (α-SMA), filamentous (F)-actin and vimentin) measured. Results:Human milk exosomes entered benign and malignant breast cells. The greatest change in wean milk protein was in TGFβ2 (p=0.01). Exosomes with a high (but not low) level of TGFβ2 led to EMT in both cancer and benign cells, based on 1) change in cell morphology, actin cytoskeleton and loss of cell-cell junction structure and 2) increased α-SMA and vimentin and decreased E-cadherin. Conclusions:TGFβ2 is significantly upregulated in breast milk exosomes during weaning/early involution. Breast milk exosomes containing high levels of TGFβ2 induce changes in both benign and malignant breast epithelial cells consistent with the development and progression of breast cancer, suggesting a role for high TGFβ2 expressing breast milk exosomes in influencing breast cancer risk.

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GWAS in multiple myeloma pharmacogenomics

Purpose:Painful peripheral neuropathy is a frequent toxicity associated with bortezomib therapy. This study aimed to identify loci that affect susceptibility to this toxicity. Experimental Design:A genome-wide association study (GWAS) of 370,605 SNPs was performed to identify risk variants for developing severe bortezomib-induced peripheral neuropathy (BiPN) in 469 multiple myeloma (MM) patients who received bortezomib-dexamethasone therapy prior to autologous stem-cell in randomized clinical trials of the Intergroupe Francophone du Myelome (IFM) and findings were replicated in 114 MM patients of the HOVON-65/GMMG-HD4 clinical trial. Results:A single SNP in the PKNOX1 gene was associated with BiPN in the exploratory cohort (rs2839629; OR, 1.89, 95% CI: [1.45-2.44]; P = 7.6 x 10-6) and in the replication cohort (OR, 2.04; 95% CI = [1.11-3.33]; P= 8.3 x 10-3). In addition, rs2839629 is in strong linkage disequilibrium (r2 = 0.87) with rs915854, located in the intergenic region between PKNOX1 and CBS. Expression quantitative trait loci mapping showed that both rs2839629 and rs915854 genotypes impact PKNOX1 expression in nerve tissue while rs2839629 affects CBS expression in skin and blood. Conclusions:The use of GWAS in MM pharmacogenomics has identified a novel candidate genetic locus mapping to PKNOX1 and in the immediate vicinity of CBS at 21q22.3 associated with the severe bortezomib-induced toxicity. The proximity of these two genes involved in neurologic pain whose tissue-specific expression is modified by the two variants provides new targets for neuro-protective strategies.

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Early Detection Biomarkers for Ovarian Cancer

Purpose: About 60% of ovarian cancers are diagnosed at late stage, when 5-year survival is less than 30% in contrast to 90% for local disease. This has prompted search for early detection biomarkers. For initial testing, specimens taken months or years before ovarian cancer diagnosis are the best source of information to evaluate early detection biomarkers. Here we evaluate the most promising ovarian cancer screening biomarkers in prospectively collected samples from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Experimental Design: We measured CA125, HE4, CA72.4 and CA15.3 in 810 invasive epithelial ovarian cancer cases and 1,939 controls. We calculated the sensitivity at 95% and 98% specificity as well as Area under the Receiver Operator Curve (C-statistic) for each marker individually and in combination. Additionally, we evaluated marker performance by stage at diagnosis and time between blood draw and diagnosis. Results: We observed the best discrimination between cases and controls within six months of diagnosis for CA125 (C-statistic=0.92), HE4 (0.84), CA72.4 (0.77), and CA15.3 (0.73). Marker performance declined with longer time between blood draw and diagnosis and for earlier staged disease. However, assessment of discriminatory ability at early stage was limited by small numbers. Combinations of markers performed modestly, but significantly better than any single marker. Conclusions: CA125 remains the single best marker for the early detection of invasive epithelial ovarian cancer, but can be slightly improved by combining with other markers. Identifying novel markers for ovarian cancer will require studies including larger numbers of early stage cases.

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Subclonal and clonal gene mutations in CLL

Purpose: CLL-associated gene mutations that influence CLL cell fitness and chemotherapy resistance should increase in clonal representation when measured before therapy and at relapse. Experimental Design: To uncover mutations associated with CLL relapse, we have performed whole exome sequencing (WES) in a discovery cohort of sixty-one relapsed CLL patients identifying eighty-six recurrently mutated genes. The variant allele fractions (VAFs) of nineteen genes with mutations in {greater than or equal to} 3/61 cases were measured in fifty-three paired pre- and post-treatment CLL samples sorted to purity using panel-based deep re-sequencing or by droplet digital PCR (ddPCR). Results: We identify mutations in TP53 as the dominant subclonal gene driver of relapsed CLL often demonstrating substantial increases in VAFs. Subclonal mutations in SAMHD1 also recurrently demonstrated increased VAFs at relapse. Mutations in ATP10A, FAT3, FAM50A and MGA, although infrequent, demonstrated enrichment in {greater than or equal to}2 cases each. In contrast, mutations in NOTCH1, SF3B1, POT1, FBXW7, MYD88, NXF1, XPO1, ZMYM3 or CHD2 were predominantly already clonal prior to therapy indicative of a pre-treatment pathogenetic driver role in CLL. Quantitative analyses of clonal dynamics uncovers rising, stable and falling clones and subclones without clear evidence that gene mutations other than in TP53 and possibly SAMHD1 are frequently selected for at CLL relapse. Conclusion: Data in aggregate support a provisional categorization of CLL-associated recurrently mutated genes into three classes i) often subclonal pre-therapy and strongly enriched after therapy, or, ii) mostly clonal pre-therapy or without further enrichments at relapse, or, iii) subclonal before and after therapy and enriching only in sporadic cases.

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Defining castration-resistant prostate cancer stem cells

Purpose: We have shown that the phenotypically undifferentiated (PSA-/lo) prostate cancer (PCa) cell population harbors long-term self-renewing cancer stem cells (CSCs) that resist castration and a subset of the cells within PSA-/lo population bearing the ALDHhiCD44+α2β1+ phenotype (Triple Marker+/TM+) is capable of robustly initiating xenograft tumors in castrated mice. The goal of the current project is to further characterize the biological properties of TM+ PCa cell population, particularly in the context of initiating and propagating CRPC. Experimental Design: The in vivo CSC activities were measured by limiting-dilution serial tumor transplantation assays in both androgen-dependent (AD) and androgen-independent (AI) PCa xenograft models. In vitro clonal, clonogenic and sphere-formation assays were conducted in cells purified from xenograft and patient tumors. qPCR, Western blot, lentiviral-mediated gene knockdown, and human microRNA arrays were performed for mechanistic studies. Results: By focusing on LAPC9 model, we show that the TM+ cells are CSCs with both tumor-initiating and tumor-propagating abilities for CRPC. Moreover, primary patient samples have TM+ cells, which possess CSC activities in 'castrated' culture conditions. Mechanistically, we find that 1) the phenotypic markers are causally involved in CRPC development; 2) the TM+ cells preferentially express castration resistance and stem cell-associated molecules that regulate their CSC characteristics; and 3) the TM+ cells possess distinct microRNA expression profiles and miR-499-5p functions as an oncomir. Conclusions: Our results define the TM+ PCa cells as a population of pre-existent stem-like cancer cells that can both mediate and propagate CRPC and highlight the TM+ cell population as a therapeutic target.

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AKT1 and BRAF mutations in pediatric aggressive fibromatosis

Abstract

Aside from the CTNNB1 and adenomatous polyposis coli (APC) mutations, the genetic profile of pediatric aggressive fibromatosis (AF) has remained poorly characterized. The aim of this study was to shed more light on the mutational spectrum of pediatric AF, comparing it with its adult counterpart, with a view to identifying biomarkers for use as prognostic factors or new potential therapeutic targets. CTNNB1, APC, AKT1, BRAF TP53, and RET Sanger sequencing and next-generation sequencing (NGS) with the 50-gene Ion AmpliSeq Cancer Hotspot Panel v2 were performed on formalin-fixed samples from 28 pediatric and 33 adult AFs. The prognostic value of CTNNB1, AKT1, and BRAF mutations in pediatric AF patients was investigated. Recurrence-free survival (RFS) curves were estimated with the Kaplan–Meier method and statistical comparisons were drawn using the log-rank test. In addition to the CTNNB1 mutation (64%), pediatric AF showed AKT1 (31%), BRAF (19%), and TP53 (9%) mutations, whereas only the CTNNB1 mutation was found in adult AF. The polymorphism Q472H VEGFR was identified in both pediatric (56%) and adult (40%) AF. Our results indicate that the mutational spectrum of pediatric AF is more complex than that of adult AF, with multiple gene mutations involving not only CTNNB1 but also AKT1 and BRAF. This intriguing finding may have clinical implications and warrants further investigations.

The aim of this study was to shed more light on the mutational spectrum of 28 pediatric aggressive fibromatosis (AF), comparing it with its adult counterpart. In addition to CTNNB1 mutation (64%), pediatric AF showed AKT1 (31%), BRAF (19%), and TP53 (9%) mutations, whereas only the CTNNB1 mutation was found in 33 adult AF. This intriguing finding, suggesting a mutational spectrum of pediatric AF more complex than that of adult, may have clinical implications and warrants further investigations.

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Developing physical frailty specifications for investigation of frailty pathways in older people

Abstract

Different frailty definitions are suitable for different purposes. When investigating its key multidimensional predictors and effects, narrower definitions of frailty that exclude these elements may be more desirable. For this purpose, candidate physical frailty specifications are constructed and then evaluated on their construct and concurrent validity. For 4638 participants aged 65 to 89 years from wave 2 (2004) of the English Longitudinal Study of Ageing, confirmatory factor analysis is performed to create physical frailty specifications with four indicators (slowness, weakness, exhaustion, and weight loss) and with three indicators (slowness, weakness, and either exhaustion or weight loss). Using derived factor scores, their convergent, discriminant, and concurrent validity are compared. For specifications with four indicators and with three indicators including exhaustion, slowness contributes dominantly to the physical frailty factor. However, with three indicators including weight loss, weakness contributes most. Where represented, weight loss only contributes minimally. Higher factor scores are significantly associated with chronic diseases, functional impairment, and poor self-rated health, although less so for the third specification. Factor scores for the first two specifications have low correlation with psychological and social frailty while those for the third have negligible correlation. Factor scores increase with higher Frailty Index although again less so for the third specification. Minor differences are seen across gender. On account of their convergent, discriminatory, and concurrent validity, physical frailty specifications with four indicators and with three indicators including exhaustion hold promise for use in investigation of frailty pathways involving multidimensional predictors and effects.

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A case of video-assisted thoracoscopic radical esophagectomy for cancer in a patient with essential thrombocythemia

Abstract

A 73-year-old man was diagnosed with essential thrombocythemia and treated with acetylsalicylic acid and hydroxyurea for 15 years. He was referred to our hospital for treatment of esophageal cancer detected by endoscopy. The cancer stage was T1N1M0, cStage IIB according to the classification of the Union for International Cancer Control, 7th edition. After administering two courses of preoperative chemotherapy (5-fluorouracil + cisplatin), the patient underwent video-assisted thoracoscopic radical esophagectomy. Hydroxyurea administration was discontinued during anticancer therapy and restarted to control the platelet count. Heparin was continuously infused during the perioperative period, and hydroxyurea was restarted through a jejunostomy tube on the postoperative day 2. No thrombosis or hemorrhage developed, and the patient was discharged from the hospital on the postoperative day 33. This is the first case report of video-assisted thoracoscopic radical esophagectomy for esophageal cancer in a patient with essential thrombocythemia.

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Feasibility and Outcomes of Oncology Teaching for 5th Year Medical Students

Abstract

This study explored medical students' opinions of undergraduate oncology teaching, aiming to define optimal strategies for nonspecialist oncology teaching. A cross-sectional study was conducted at Al Imam Muhammed Ibn Saud Islamic University, Riyadh, Saudi Arabia. Between August 2014 and June 2015, 124 medical students completing the oncology course in the fifth year at the College of Medicine, Al Imam Muhammed Ibn Saud Islamic University, were given a 47-item questionnaire. One hundred and five students completed the questionnaire. Students reported that the oncology teaching fitted well with the course and that they gained knowledge and clinical skills, including understanding of how to break bad news. There was no consensus regarding whether physicians had an ongoing responsibility of care if patients were unable to embrace the treatment offered and whether pain was adequately controlled in patients with cancer. There was good understanding of the ethics of analgesia use and the need to involve patients in the decision-making process. There was a wide spread of opinion when asked if the physician should "decide for themselves how much information to give." Forty-four percent of students stated that they would attend an oncology summer school. This study shows the undergraduate oncology course to be effective in teaching knowledge, ethics, and skills and to be well received by fifth year medical students. Inclusion of appropriate teaching in medical school curricula may be the most effective way to ensure all clinicians acquire appropriate training in oncology.

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Safety and clinical activity of vascular endothelial growth factor receptor (VEGFR)- tyrosine kinase inhibitors after programmed cell death 1 inhibitor treatment in patients with metastatic clear cell renal cell carcinoma

There is limited data on the efficacy and safety of VEGFR-TKI after PD-1 inhbition. This multi-institutional and retrospective study included 70 patients with metastatic clear renal cell carcinoma (mRCC) enrolled in three prospective trials evaluating aPD-1 therapy. Patients received aPD-1 monotherapy or aPD-1 in combination with VEGFR-TKI or Ipilimumab and subsequently were treated with VEGFR-TKIs. By the Memorial Sloan Kettering Cancer Center prognostic risk group criteria, 30% of the patients were favorable risk, 27.1% were intermediate risk and 27.1% were poor risk. The objective response rate (ORR) for VEGFR -TKI therapy after PD-1 inhibition was 28.4% and the median PFS was of 6.4 months (4.3-9.5). Patient treated with immune checkpoint inhibitors alone were more likely to achieve an objective response than those treated with aPD-1 in combination with VEGFR-TKI (OR=5.38; 95% CI=1.12-26.0, p=0.03). There was a trend toward numerically longer median PFS in the VEGFR-TKI after CPI alone group, 8.4 mo (3.2-12.4) compared to 5.5 mo (2.9-8.3) for those who had VEGFR-TKI after aPD-1 in combination with VEGFR-TKI (p=0.15). The most common adverse events were asthenia, hypertension and diarrhea. Treatment with VEGFR-TKIs has clinical activity and can be done safely after PD-1 inhibition in this selected population of patients with mRCC. ORR with VEGFR-TKIS was significantly lower and a trend towards shorter mPFS was noted in patients who received prior aPD-1 in combination with VEGFR-TKI. PD-1 exposure does not seem to influence the safety of subsequent VEGFR-TKI treatment.

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Co-option of Liver Vessels and Not Sprouting Angiogenesis Drives Acquired Sorafenib Resistance in Hepatocellular Carcinoma

Background: The anti-angiogenic Sorafenib is the only approved systemic therapy for advanced hepatocellular carcinoma (HCC). However, acquired resistance limits its efficacy. An emerging theory to explain intrinsic resistance to other anti-angiogenic drugs is 'vessel co-option,' ie, the ability of tumors to hijack the existing vasculature in organs such as the lungs or liver, thus limiting the need for sprouting angiogenesis. Vessel co-option has not been evaluated as a potential mechanism for acquired resistance to anti-angiogenic agents.

Methods: To study sorafenib resistance mechanisms, we used an orthotopic human HCC model (n = 4-11 per group), where tumor cells are tagged with a secreted protein biomarker to monitor disease burden and response to therapy. Histopathology, vessel perfusion assessed by contrast-enhanced ultrasound, and miRNA sequencing and quantitative real-time polymerase chain reaction were used to monitor changes in tumor biology.

Results: While sorafenib initially inhibited angiogenesis and stabilized tumor growth, no angiogenic 'rebound' effect was observed during development of resistance unless therapy was stopped. Instead, resistant tumors became more locally infiltrative, which facilitated extensive incorporation of liver parenchyma and the co-option of liver-associated vessels. Up to 75% (±10.9%) of total vessels were provided by vessel co-option in resistant tumors relative to 23.3% (±10.3%) in untreated controls. miRNA sequencing implicated pro-invasive signaling and epithelial-to-mesenchymal-like transition during resistance development while functional imaging further supported a shift from angiogenesis to vessel co-option.

Conclusions: This is the first documentation of vessel co-option as a mechanism of acquired resistance to anti-angiogenic therapy and could have important implications including the potential therapeutic benefits of targeting vessel co-option in conjunction with vascular endothelial growth factor receptor signaling.

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Evidence Showing That Tumors Can Grow Without Angiogenesis and Can Switch Between Angiogenic and Nonangiogenic Phenotypes

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The Conundrum of Genetic "Drivers" in Benign Conditions

Advances in deep genomic sequencing have identified a spectrum of cancer-specific passenger and driver aberrations. Clones with driver anomalies are believed to be positively selected during carcinogenesis. Accumulating evidence, however, shows that genomic alterations, such as those in BRAF, RAS, EGFR, HER2, FGFR3, PIK3CA, TP53, CDKN2A, and NF1/2, all of which are considered hallmark drivers of specific cancers, can also be identified in benign and premalignant conditions, occasionally at frequencies higher than in their malignant counterparts. Targeting these genomic drivers can produce dramatic responses in advanced cancer, but the effects on their benign counterparts are less clear. This benign-malignant phenomenon is well illustrated in studies of BRAF V600E mutations, which are paradoxically more frequent in benign nevi (~80%) than in dysplastic nevi (~60%) or melanoma (~40%-45%). Similarly, human epidermal growth factor receptor 2 is more commonly overexpressed in ductal carcinoma in situ (~27%-56%) when compared with invasive breast cancer (~11%-20%). FGFR3 mutations in bladder cancer also decrease with tumor grade (low-grade tumors, ~61%; high-grade, ~11%). "Driver" mutations also occur in nonmalignant settings: TP53 mutations in synovial tissue from rheumatoid arthritis and FGFR3 mutations in seborrheic keratosis. The latter observations suggest that the oncogenicity of these alterations may be tissue context–dependent. The conversion of benign conditions to premalignant disease may involve other genetic events and/or epigenetic reprogramming. Putative driver mutations can also be germline and associated with increased cancer risk (eg, germline RAS or TP53 alterations), but germline FGFR3 or NF2 abnormalities do not predispose to malignancy. We discuss the enigma of genetic "drivers" in benign and premalignant conditions and the implications for prevention strategies and theories of tumorigenesis.

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