Predictors of survival in patients with sarcoma admitted to the intensive care unit

Abstract

Background

Advances in treatment of sarcoma patients has prolonged survival but has led to increased disease- or treatment-related complications resulting in greater number of admissions to the intensive care unit (ICU). Survival and long-term outcome information about such critically ill patients with sarcoma is unknown.

Methods

The primary objective of the study was to determine the ICU and post-ICU survival rates of critically ill sarcoma patients. Secondary objectives included determining the modifiable and non-modifiable predictors of poor survival. We performed a retrospective chart review of sarcoma patients admitted to the ICU at The University of Texas MD Anderson Cancer Center between January 1, 2005, and December 31, 2012. Main outcome measures were ICU mortality, in-hospital mortality and 1, 2, and 6-month survival rates. Covariates such as histological diagnosis, disease characteristics, chemotherapy use, Charlson comorbidity index, Sequential Organ Failure Assessment (SOFA) scores, and clinical findings leading to ICU admission were analyzed for their effects on survival.

Results

We identified 172 admissions over the 8-year study period hat met our inclusion criteria. The study population was 45.9 % males with a median age of 52 years. The most common sarcoma subgroups were high-grade unclassified sarcoma (25 %) and bone tumors (17.4 %). The ICU mortality rate was 23.3 % (95 % confidence interval [CI], 16.9–29.6 %), and an additional 6.4 % of patients died before hospital discharge (95 % CI, 22.9–37.1 %). 6-month OS rates were 41 %. The median SOFA scores on admission were 6 (inter quartile range (IQR), 3.5–9) in ICU survivors and 10 (IQR, 6.5–14) in ICU non-survivors. Increase in SOFA scores ≥6 led to poor outcomes (ICU survival 13.3 %, OS 6.7 %). Charlson comorbidity index (HR 1.139, 95 % CI 1.023–1.268, p = 0.02) and discharge SOFA scores (HR 1.210, 95 % CI 1.141–1.283, p < 0.0001) correlated with overall survival.

Conclusions

Our results suggest that patients that are admitted to the ICU for respiratory failure, cardiac arrest, septic shock, acute renal failure or acidosis and also have a high SOFA score with subsequent worsening in the ICU have poor prognosis. Based on the retrospective data which needs further validation we can recommend that judicious approach should be taken in patients with predictors of poor survival before subjecting them to aggressive treatment.

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Role of the CYFIP1-NCKAP1 complex in metastasis

Inactivation of the WASF3 gene suppresses invasion and metastasis of breast cancer cells. WASF3 function is regulated through a protein complex that includes the NCKAP1 and CYFIP1 proteins. Here we report that silencing NCKAP1 destabilizes the WASF3 complex, resulting in a suppression of the invasive capacity of breast, prostate and colon cancer cells. In an in vivo model of spontaneous metastasis in immunocompromized mice, loss of NCKAP1 also suppresses metastasis. Activation of the WASF protein complex occurs through interaction with RAC1, and inactivation of NCKAP1 prevents the association of RAC1 with the WASF3 complex. Thus, WASF3 depends on NCKAP1 to promote invasion and metastasis. Here we show that stapled peptides targeting the interface between NCKAP1 and CYFIP1 destabilize the WASF3 complex and suppress RAC1 binding, thereby suppressing invasion. Using a complex-disrupting compound identified in this study termed WANT3, our results offer a mechanistic proof of concept to target this interaction as a novel approach to inhibit breast cancer metastasis.

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Mobile Genetic Elements in Cancer

Approximately half of the human genome consists of repetitive sequence attributed to the activities of mobile DNAs, including DNA transposons, RNA transposons, and endogenous retroviruses. Of these, only long interspersed elements (LINE-1 or L1) and sequences copied by LINE-1 remain mobile in our species today. Although cells restrict L1 activity by both transcriptional and posttranscriptional mechanisms, L1 derepression occurs in developmental and pathologic contexts, including many types of cancers. However, we have limited knowledge of the extent and consequences of L1 expression in premalignancies and cancer. Participants in this NIH strategic workshop considered key questions to enhance our understanding of mechanisms and roles the mobilome may play in cancer biology. Cancer Res; 76(15); 1–4. ©2016 AACR.

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TRAP1 and SDH as Therapeutic Targets of HCC

S-nitrosoglutathione reductase (GSNOR) represents the best-documented denitrosylase implicated in regulating the levels of proteins posttranslationally modified by nitric oxide on cysteine residues by S-nitrosylation. GSNOR controls a diverse array of physiologic functions, including cellular growth and differentiation, inflammation, and metabolism. Chromosomal deletion of GSNOR results in pathologic protein S-nitrosylation that is implicated in human hepatocellular carcinoma (HCC). Here we identify a metabolic hallmark of aberrant S-nitrosylation in HCC and exploit it for therapeutic gain. We find that hepatocyte GSNOR deficiency is characterized by mitochondrial alteration and by marked increases in succinate dehydrogenase (SDH) levels and activity. We find that this depends on the selective S-nitrosylation of Cys501 in the mitochondrial chaperone TRAP1, which mediates its degradation. As a result, GSNOR-deficient cells and tumors are highly sensitive to SDH inhibition, namely to α-tocopheryl succinate, an SDH-targeting molecule that induced RIP1/PARP1-mediated necroptosis and inhibited tumor growth. Our work provides a specific molecular signature of aberrant S-nitrosylation in HCC, a novel molecular target in SDH, and a first-in-class therapy to treat the disease. Cancer Res; 76(14); 4170–82. ©2016 AACR.

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Year 1993 in Colon Cancer Genetics

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Targeting a Glycolysis HIF-1 Feed-Forward Loop

The hypoxia-inducible transcription factor HIF1α drives expression of many glycolytic enzymes. Here, we show that hypoxic glycolysis, in turn, increases HIF1α transcriptional activity and stimulates tumor growth, revealing a novel feed-forward mechanism of glycolysis-HIF1α signaling. Negative regulation of HIF1α by AMPK1 is bypassed in hypoxic cells, due to ATP elevation by increased glycolysis, thereby preventing phosphorylation and inactivation of the HIF1α transcriptional coactivator p300. Notably, of the HIF1α-activated glycolytic enzymes we evaluated by gene silencing, aldolase A (ALDOA) blockade produced the most robust decrease in glycolysis, HIF-1 activity, and cancer cell proliferation. Furthermore, either RNAi-mediated silencing of ALDOA or systemic treatment with a specific small-molecule inhibitor of aldolase A was sufficient to increase overall survival in a xenograft model of metastatic breast cancer. In establishing a novel glycolysis–HIF-1α feed-forward mechanism in hypoxic tumor cells, our results also provide a preclinical rationale to develop aldolase A inhibitors as a generalized strategy to treat intractable hypoxic cancer cells found widely in most solid tumors. Cancer Res; 76(14); 4259–69. ©2016 AACR.

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Biology of H. pylori CagA

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K14 HPV49 E6/E7 Transgenic Mice

The beta genus of human papillomaviruses (ß-HPV) includes approximately 50 different viral types that are subdivided into five species (ß-1 through ß-5). Nonmelanoma cancers may involve some ß-1 and ß-2 HPV types, but the biology of most ß-HPV types and their possible connections to human disease are still little characterized. In this study, we studied the effects of ß-3 type HPV49 in a novel transgenic (Tg) mouse model, using a cytokeratin K14 promoter to drive expression of the E6 and E7 genes from this virus in the basal skin epidermis and the mucosal epithelia of the digestive tract (K14 HPV49 E6/E7-Tg mice). Viral oncogene expression only marginally increased cellular proliferation in the epidermis of Tg animals, compared with wild-type littermates, and we observed no spontaneous tumor formation during their entire lifespan. However, we found that K14 HPV49 E6/E7-Tg mice were highly susceptible to upper digestive tract carcinogenesis upon initiation with 4-nitroquinoline 1-oxide (4NQO). This was a selective effect, as the same mice did not exhibit any skin lesions after chronic UV irradiation. Opposite results were observed in an analogous Tg model expressing the ß-2 HPV38 E6 and E7 oncogenes at the same anatomic sites. While these mice were highly susceptible to UV-induced skin carcinogenesis, as previously shown, they were little affected by 4NQO treatment. Overall, our findings highlight important differences in the biologic properties of certain ß-type HPV that affect their impact on carcinogenesis in an anatomic site-specific manner. Cancer Res; 76(14); 4216–25. ©2016 AACR.

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Exercise in Cancer Initiation, Progression, and Metastasis

A major objective of the emerging field of exercise–oncology research is to determine the efficacy of, and biological mechanisms by which, aerobic exercise affects cancer incidence, progression, and/or metastasis. There is a strong inverse association between self-reported exercise and the primary incidence of several forms of cancer; similarly, emerging data suggest that exercise exposure after a cancer diagnosis may improve outcomes for early-stage breast, colorectal, or prostate cancer. Arguably, critical next steps in the development of exercise as a candidate treatment in cancer control require preclinical studies to validate the biological efficacy of exercise, identify the optimal "dose", and pinpoint mechanisms of action. To evaluate the current evidence base, we conducted a critical systematic review of in vivo studies investigating the effects of exercise in cancer prevention and progression. Studies were evaluated on the basis of tumor outcomes (e.g., incidence, growth, latency, metastasis), dose–response, and mechanisms of action, when available. A total of 53 studies were identified and evaluated on tumor incidence (n = 24), tumor growth (n = 33), or metastasis (n = 10). We report that the current evidence base is plagued by considerable methodologic heterogeneity in all aspects of study design, endpoints, and efficacy. Such heterogeneity precludes meaningful comparisons and conclusions at present. To this end, we provide a framework of methodologic and data reporting standards to strengthen the field to guide the conduct of high-quality studies required to inform translational, mechanism-driven clinical trials. Cancer Res; 76(14); 4032–50. ©2016 AACR.

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Highlights from Recent Cancer Literature

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Adipocyte Exosomes: A New Link between Obesity and Cancer

Malignant progression results from a dynamic cross-talk between stromal and cancer cells. Recent evidence suggests that this cross-talk is mediated to a significant extent by exosomes, nanovesicles secreted by most cell types and which allow the transfer of proteins, lipids, and nucleic acids between cells. Adipocytes are a major component of several tumor microenvironments, including that of invasive melanoma, where cells have migrated to the adipocyte-rich hypodermic layer of the skin. We show that adipocytes secrete exosomes in abundance, which are then taken up by tumor cells, leading to increased migration and invasion. Using mass spectrometry, we analyzed the proteome of adipocyte exosomes. Interestingly, these vesicles carry proteins implicated in fatty acid oxidation (FAO), a feature highly specific to adipocyte exosomes. We further show that, in the presence of adipocyte exosomes, FAO is increased in melanoma cells. Inhibition of this metabolic pathway completely abrogates the exosome-mediated increase in migration. Moreover, in obese mice and humans, both the number of exosomes secreted by adipocytes as well as their effect on FAO-dependent cell migration are amplified. These observations might in part explain why obese melanoma patients have a poorer prognosis than their nonobese counterparts. Cancer Res; 76(14); 4051–7. ©2016 AACR.

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Regulation of AR by miR-320

Targeting androgen receptor (AR) by pharmacologic intervention is one of the effective approaches for treatment of malignant prostate cancers. Histone deacetylase (HDAC) alters the epigenetic status of tumor-associated genes, including those for miRNAs (miRNA), and affects the behavior of cancers. Here, we examined the molecular effects of a HDAC inhibitor, OBP-801, on AR expression and tumor cell growth in prostate cancers. Treatment with OBP-801 efficiently suppressed cell growth of three prostate cancer lines (22Rv1, VCaP, and LNCaP), together with AR downregulation, regardless of their hormone sensitivity. Intriguingly, this effect by OBP-801 was not due to decreased transcriptional activity of the AR gene, but due to posttranscriptional regulation, namely by miRNA-mediated suppression. Among the upregulated miRNAs after OBP-801 treatment in the three prostate cancer cell lines, miR-320a, whose expression was significantly correlated with prognosis of prostate cancers (P = 0.0185), was the most closely associated with AR expression. An miR-320a mimic suppressed AR protein expression together with growth suppression, while anti-miR-320a oligonucleotide significantly abrogated the growth suppression by OBP-801 treatment. FISH analysis revealed that miR-320a was highly expressed in human normal prostate luminal cells, but was rarely expressed in prostate cancer cells. In an AR-dependent prostate tumorigenic rat model, OBP-801 treatment profoundly increased miR-320a expression and repressed prostate tumorigenesis. Our data demonstrated that OBP-801 effectively suppressed AR activity via epigenetic upregulation of miR-320a, which resulted in tumor cell growth suppression of prostate cancers. OBP-801 may be a potent AR-targeting therapeutic reagent in AR-positive prostate cancer regardless of androgen dependency. Cancer Res; 76(14); 4192–204. ©2016 AACR.

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Metabolic Reprogramming of Cancer Cells

Somatic copy number alterations frequently occur in the cancer genome affecting not only oncogenic or tumor suppressive genes, but also passenger and potential codriver genes. An intrinsic feature resulting from such genomic perturbations is the deregulation in the metabolism of tumor cells. In this study, we have shown that metabolic and cancer-causing genes are unexpectedly often proximally positioned in the chromosome and share loci with coaltered copy numbers across multiple cancers (19 cancer types from The Cancer Genome Atlas). We have developed an analysis pipeline, Identification of Metabolic Cancer Genes (iMetCG), to infer the functional impact on metabolic remodeling from such coamplifications and codeletions and delineate genes driving cancer metabolism from those that are neutral. Using our identified metabolic genes, we were able to classify tumors based on their tissue and developmental origins. These metabolic genes were similar to known cancer genes in terms of their network connectivity, isoform frequency, and evolutionary features. We further validated these identified metabolic genes by (i) using gene essentiality data from several tumor cell lines, (ii) showing that these identified metabolic genes are strong indicators for patient survival, and (iii) observing a significant overlap between our identified metabolic genes and known cancer-metabolic genes. Our analyses revealed a hitherto unknown generic mechanism for large-scale metabolic reprogramming in cancer cells based on linear gene proximities between cancer-causing and -metabolic genes. We have identified 119 new metabolic cancer genes likely to be involved in rewiring cancer cell metabolism. Cancer Res; 76(14); 4058–67. ©2016 AACR.

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Metastasis Suppression by E6AP

Metastatic disease is the major cause of breast cancer–related death and despite many advances, current therapies are rarely curative. Tumor cell migration and invasion require actin cytoskeletal reorganization to endow cells with capacity to disseminate and initiate the formation of secondary tumors. However, it is still unclear how these migratory cells colonize distant tissues to form macrometastases. The E6-associated protein, E6AP, acts both as an E3 ubiquitin-protein ligase and as a coactivator of steroid hormone receptors. We report that E6AP suppresses breast cancer invasiveness, colonization, and metastasis in mice, and in breast cancer patients, loss of E6AP associates with poor prognosis, particularly for basal breast cancer. E6AP regulates actin cytoskeletal remodeling via regulation of Rho GTPases, acting as a negative regulator of ECT2, a GEF required for activation of Rho GTPases. E6AP promotes ubiquitination and proteasomal degradation of ECT2 for which high expression predicts poor prognosis in breast cancer patients. We conclude that E6AP suppresses breast cancer metastasis by regulating actin cytoskeleton remodeling through the control of ECT2 and Rho GTPase activity. These findings establish E6AP as a novel suppressor of metastasis and provide a compelling rationale for inhibition of ECT2 as a therapeutic approach for patients with metastatic breast cancer. Cancer Res; 76(14); 4236–48. ©2016 AACR.

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AU-Rich Elements-Protein Interactions in Cancer

Defects in AU-rich elements (ARE)-mediated posttranscriptional control can lead to several abnormal processes that underlie carcinogenesis. Here, we performed a systematic analysis of ARE-mRNA expression across multiple cancer types. First, the ARE database (ARED) was intersected with The Cancer Genome Atlas databases and others. A large set of ARE-mRNAs was over-represented in cancer and, unlike non-ARE-mRNAs, correlated with the reversed balance in the expression of the RNA-binding proteins tristetraprolin (TTP, ZFP36) and HuR (ELAVL1). Serial statistical and functional enrichment clustering identified a cluster of 11 overexpressed ARE-mRNAs (CDC6, KIF11, PRC1, NEK2, NCAPG, CENPA, NUF2, KIF18A, CENPE, PBK, TOP2A) that negatively correlated with TTP/HuR mRNA ratios and was involved in the mitotic cell cycle. This cluster was upregulated in a number of solid cancers. Experimentally, we demonstrated that the ARE-mRNA cluster is upregulated in a number of tumor breast cell lines when compared with noninvasive and normal-like breast cancer cells. RNA-IP demonstrated the association of the ARE-mRNAs with TTP and HuR. Experimental modulation of TTP or HuR expression led to changes in the mitosis ARE-mRNAs. Posttranscriptional reporter assays confirmed the functionality of AREs. Moreover, TTP augmented mitotic cell-cycle arrest as demonstrated by flow cytometry and histone H3 phosphorylation. We found that poor breast cancer patient survival was significantly associated with low TTP/HuR mRNA ratios and correlated with high levels of the mitotic ARE-mRNA signature. These results significantly broaden the role of AREs and their binding proteins in cancer, and demonstrate that TTP induces an antimitotic pathway that is diminished in cancer. Cancer Res; 76(14); 4068–80. ©2016 AACR.

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MFG-E8 Promotes MSC-Induced Angiogenesis and TAM in Melanoma

Secretion of the powerful angiogenic factor MFG-E8 by pericytes can bypass the therapeutic effects of anti-VEGF therapy, but the mechanisms by which MFG-E8 acts are not fully understood. In this study, we investigated how this factor acts to promote the growth of melanomas that express it. We found that mouse bone marrow–derived mesenchymal stromal cells (MSC) expressed a substantial amount of MFG-E8. To assess its expression from this cell type, we implanted melanoma cells and MSC derived from wild type (WT) or MFG-E8 deficient [knockout (KO)] into mice and monitored tumor growth. Tumor growth and M2 macrophages were each attenuated in subjects coimplanted with KO-MSC compared with WT-MSC. In both xenograft tumors and clinical specimens of melanoma, we found that MFG-E8 expression was heightened near blood vessels where MSC could be found. Through in vitro assays, we confirmed that WT-MSC–conditioned medium was more potent at inducing M2 macrophage polarization, compared with KO-MSC–conditioned medium. VEGF and ET-1 expression in KO-MSC was significantly lower than in WT-MSC, correlating in vivo with reduced tumor growth and numbers of pericytes and M2 macrophages within tumors. Overall, our results suggested that MFG-E8 acts at two levels, by increasing VEGF and ET-1 expression in MSC and by enhancing M2 polarization of macrophages, to increase tumor angiogenesis. Cancer Res; 76(14); 4283–92. ©2016 AACR.

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Monitoring Antiangiogenic Treatment with 3D USMI

Three-dimensional (3D) imaging capabilities to assess responses to anticancer therapies are needed to minimize sampling errors common to two-dimensional approaches as a result of spatial heterogeneity in tumors. Recently, the feasibility and reproducibility of 3D ultrasound molecular imaging (3D USMI) using contrast agents, which target molecular markers, have greatly improved, due to the development of clinical 3D matrix array transducers. Here we report preclinical proof-of-concept studies showing that 3D USMI of VEGFR2/KDR expression accurately gauges longitudinal treatment responses to antiangiogenesis therapy in responding versus nonresponding mouse models of colon cancer. Tumors in these models exhibited differential patterns of VEGFR2-targeted 3D USMI signals during the course of antiangiogenic treatment with bevacizumab. In responding tumors, the VEGFR2 signal decreased as soon as 24 hours after therapy was started, whereas in nonresponding tumors there was no change in signal at any time point. The early decrease in VEGFR2 signal was highly predictive of treatment outcome at the end of therapy. Our results offer preclinical proof that 3D USMI can predict responses to antiangiogenic therapy, warranting further investigation of its clinical translatability to predicting treatment outcomes in patients. Cancer Res; 76(14); 4081–9. ©2016 AACR.

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miR-29b Mediates KRAS Signaling in NSCLC

A global understanding of miRNA function in EGFR signaling pathways may provide insights into improving the management of KRAS-mutant lung cancers, which remain relatively recalcitrant to treatment. To identify miRNAs implicated in EGFR signaling, we transduced bronchial epithelial BEAS-2B cells with retroviral vectors expressing KRASG12V and monitored miRNA expression patterns by microarray analysis. Through this approach, we defined miR-29b as an important target for upregulation by mutant KRAS in non–small cell lung cancers. Cell biologic analyses showed that pharmacologic inhibition of EGFR or MEK was sufficient to reduce levels of miR-29b, while PI3K inhibition had no effect. In KRASG12V-transduced BEAS-2B cells, introduction of anti-miR-29b constructs increased the sensitivity to apoptosis, arguing that miR-29b mediated apoptotic resistance conferred by mutant KRAS. Mechanistic investigations traced this effect to the ability of miR-29b to target TNFAIP3/A20, a negative regulator of NF-κB signaling. Accordingly, overexpression of an miR-29b–refractory isoform of TNFAIP3 restored NF-κB and extrinsic apoptosis, confirming that TNFAIP3 is a functionally relevant target of miR-29b. We also noted that miR-29b could confer sensitivity to intrinsic apoptosis triggered by exposure to cisplatin, a drug used widely in lung cancer treatment. Thus, miR-29b expression may tilt cells from extrinsic to intrinsic mechanisms of apoptosis. Overall, our results reveal a complexity in cancer for miR-29b, which can act as either an oncogene or tumor suppressor gene depending on signaling context. Cancer Res; 76(14); 4160–9. ©2016 AACR.

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A DCLK1-Derived miRNA Signature Predicts GI Cancer Survival

Doublecortin-like kinase 1 (DCLK1) is a gastrointestinal (GI) tuft cell kinase that has been investigated as a biomarker of cancer stem–like cells in colon and pancreatic cancers. However, its utility as a biomarker may be limited in principle by signal instability and dilution in heterogeneous tumors, where the proliferation of diverse tumor cell lineages obscures the direct measurement of DCLK1 activity. To address this issue, we explored the definition of a miRNA signature as a surrogate biomarker for DCLK1 in cancer stem–like cells. Utilizing RNA/miRNA-sequencing datasets from the Cancer Genome Atlas, we identified a surrogate 15-miRNA expression signature for DCLK1 activity across several GI cancers, including colon, pancreatic, and stomach cancers. Notably, Cox regression and Kaplan–Meier analysis demonstrated that this signature could predict the survival of patients with these cancers. Moreover, we identified patient subgroups that predicted the clinical utility of this DCLK1 surrogate biomarker. Our findings greatly strengthen the clinical significance for DCLK1 expression across GI cancers. Further, they provide an initial guidepost toward the development of improved prognostic biomarkers or companion biomarkers for DCLK1-targeted therapies to eradicate cancer stem–like cells in these malignancies. Cancer Res; 76(14); 4090–9. ©2016 AACR.

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Targeting MMR-Deficient Cancers

Impairing the division of cancer cells with genotoxic small molecules has been a primary goal to develop chemotherapeutic agents. However, DNA mismatch repair (MMR)-deficient cancer cells are resistant to most conventional chemotherapeutic agents. Here we have identified baicalein as a small molecule that selectively kills MutSα-deficient cancer cells. Baicalein binds preferentially to mismatched DNA and induces a DNA damage response in a MMR-dependent manner. In MutSα-proficient cells, baicalein binds to MutSα to dissociate CHK2 from MutSα leading to S-phase arrest and cell survival. In contrast, continued replication in the presence of baicalein in MutSα-deficient cells results in a high number of DNA double-strand breaks and ultimately leads to apoptosis. Consistently, baicalein specifically shrinks MutSα-deficient xenograft tumors and inhibits the growth of AOM-DSS–induced colon tumors in colon-specific MSH2 knockout mice. Collectively, baicalein offers the potential of an improved treatment option for patients with tumors with a DNA MMR deficiency. Cancer Res; 76(14); 4183–91. ©2016 AACR.

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New anti-cancer chemicals Ertredin and its derivatives, regulate oxidative phosphorylation and glycolysis and suppress sphere formation in vitro and tumor growth in EGFRvIII-transformed cells

Abstract

Background

EGFRvIII is a mutant form of the epidermal growth factor receptor gene (EGFR) that lacks exons 2–7. The resulting protein does not bind to ligands and is constitutively activated. The expression of EGFRvIII is likely confined to various types of cancer, particularly glioblastomas. Although an anti-EGFRvIII vaccine is of great interest, low-molecular-weight substances are needed to obtain better therapeutic efficacy. Thus, the purpose of this study is to identify low molecular weight substances that can suppress EGFRvIII-dependent transformation.

Methods

We constructed a new throughput screening system and searched for substances that decreased cell survival of NIH3T3/EGFRvIII spheres under 3-dimensional (3D)-culture conditions, but retained normal NIH3T3 cell growth under 2D-culture conditions. In vivo activity was examined using a mouse transplantation model, and derivatives were chemically synthesized. Functional characterization of the candidate molecules was investigated using an EGFR kinase assay, immunoprecipitation, western blotting, microarray analysis, quantitative polymerase chain reaction analysis, and measurement of lactate and ATP synthesis.

Results

In the course of screening 30,000 substances, a reagent, "Ertredin" was found to inhibit anchorage-independent 3D growth of sphere-forming cells transfected with EGFRvIII cDNA. Ertredin also inhibited sphere formation in cells expressing wild-type EGFR in the presence of EGF. However, it did not affect anchorage-dependent 2D growth of parental NIH3T3 cells. The 3D-growth-inhibitory activity of some derivatives, including those with new structures, was similar to Ertredin. Furthermore, we demonstrated that Ertredin suppressed tumor growth in an allograft transplantation mouse model injected with EGFRvIII- or wild-type EGFR-expressing cells; a clear toxicity to host animals was not observed. Functional characterization of Ertredin in cells expressing EGFRvIII indicated that it stimulated EGFRvIII ubiquitination, suppressed both oxidative phosphorylation and glycolysis under 3D conditions, and promoted cell apoptosis.

Conclusion

We developed a high throughput screening method based on anchorage-independent sphere formation induced by EGFRvIII-dependent transformation. In the course of screening, we identified Ertredin, which inhibited anchorage-independent 3D growth and tumor formation in nude mice. Functional analysis suggests that Ertredin suppresses both mitochondrial oxidative phosphorylation and cytosolic glycolysis in addition to promoting EGFRvIII degradation, and stimulates apoptosis in sphere-forming, EGFRvIII-overexpressing cells.

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MicroRNA-183 suppresses cancer stem-like cell properties in EBV-associated nasopharyngeal carcinoma

Abstract

Background

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated epithelial malignancy that exhibits distinct geographical and ethnic prevalence. Although the contemporary therapeutic approach of radio-/chemotherapy provides excellent results for patients with early-stage disease, it is far from satisfactory for those with disease remission and distant metastasis. Promising therapeutic strategies for advanced and relapsed NPC are still lacking. We recently identified and characterized a cancer stem-like cell (CSC) subpopulation in NPC that appeared to play an important role in tumor progression. Microarray analysis revealed downregulation of several stemness-inhibiting miRNAs in these CSC cells. Among these miRNAs, miR-96 and miR-183 showed the highest fold change and were selected to elucidate their role in repressing NPC CSC properties.

Methods

MiR-96 and miR-183 expression in NPC CSCs was detected by qRT-PCR. Transient and stable transfection was performed in EBV-positive NPC C666-1 cells to examine the effects of ectopic expression of miR-96 and miR-183 on repressing cell growth and CSC properties. Anchorage-dependent (colony formation) and anchorage-independent (tumor sphere formation) growths of these miR-96 and miR-183 expressing cells were determined. Expression of multiple CSC markers and related molecules were accessed by flow cytometry and Western blotting. The tumorigenicity of the stable miR-96- and miR-183-transfected NPC cells was examined in an in vivo nude mice model.

Results

Downregulation of miR-96 and miR-183 was confirmed in NPC spheroids. Using transient or stable transfection, we showed that ectopic expression of miR-96 and miR-183 suppressed cell growth and tumor sphere formation in NPC. Reduced NICD3 and NICD4 in miR-96- and miR-183-expressing NPC cells suggests the involvement of the NOTCH signaling pathway in their tumor suppressive function. Finally, we showed that the tumorigenicity of cells stably expressing miR-183 was significantly inhibited in the in vivo nude mice model.

Conclusions

miR-183 is a tumor-suppressive miRNA in EBV-associated NPC. Its abilities to suppress CSC properties in vitro and effectively reduce tumor growth in vivo shed light on its role as a potential therapeutic target.

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Phase II study of metformin for reduction of obesity-associated breast cancer risk: a randomized controlled trial protocol

Abstract

Background

Two-thirds of U.S. adult women are overweight or obese. High body mass index (BMI) and adult weight gain are risk factors for a number of chronic diseases, including postmenopausal breast cancer. The higher postmenopausal breast cancer risk in women with elevated BMI is likely to be attributable to related metabolic disturbances including altered circulating sex steroid hormones and adipokines, elevated pro-inflammatory cytokines, and insulin resistance. Metformin is a widely used antidiabetic drug that has demonstrated favorable effects on metabolic disturbances and as such may lead to lower breast cancer risk in obese women. Further, the anti-proliferative effects of metformin suggest it may decrease breast density, an accepted biomarker of breast cancer risk.

Methods/design

This is a Phase II randomized, double-blind, placebo-controlled trial of metformin in overweight/obese premenopausal women who have elements of metabolic syndrome. Eligible participants will be randomized to receive metformin 850 mg BID (n = 75) or placebo (n = 75) for 12 months. The primary endpoint is change in breast density, based on magnetic resonance imaging (MRI) acquired fat-water features. Secondary outcomes include changes in serum insulin levels, serum insulin-like growth factor (IGF)-1 to insulin-like growth factor binding protein (IGFBP)-3 ratio, serum IGF-2 levels, serum testosterone levels, serum leptin to adiponectin ratio, body weight, and waist circumference. Exploratory outcomes include changes in metabolomic profiles in plasma and nipple aspirate fluid. Changes in tissue architecture as well as cellular and molecular targets in breast tissue collected in a subgroup of participants will also be explored.

Discussion

The study will evaluate whether metformin can result in favorable changes in breast density, select proteins and hormones, products of body metabolism, and body weight and composition. The study should help determine the potential breast cancer preventive activity of metformin in a growing population at risk for multiple diseases.

Trial registration

ClinicalTrials.gov Identifier: NCT02028221. Registered on January 2, 2014. Grant #: 1R01CA172444-01A1 awarded on Sept 11, 2013.

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Characteristics and treatment of polycythemia vera patients in clinical practice: a multicenter chart review on 1476 individuals in Germany

Abstract

Purpose

Treatment recommendations for patients with polycythemia vera (PV) are well established. Most multicenter trials investigating novel therapeutic strategies for PV are developed and conducted at university hospitals and specialized academic centers. The majority of patients in Germany, however, are treated in an outpatient (ambulatory) setting. The aim of this study was to evaluate the 'real-life' situation in a cohort of 1467 patients by analyzing data from a survey conducted at private practices and primary care centers.

Methods

Eligible private practices and primary care centers treating patients with MPN were recruited to participate in a paper–pencil-based survey conducted from March 2015 until March 2016 in Germany. Hematologists were asked to report from patient charts. Descriptive analyses were conducted to assess for outcomes examined by reported prognostic risk scores, symptom scores and clinical response criteria.

Results

In total, 34 centers participated in our retrospective survey and provided data on 1476 patients. Most patients were of older age (66.7 % older than 66 years of age), which was the main risk factor according to the criteria published by Tefferi and colleagues. Molecular status at diagnosis was not evaluated in 23 % of patients. Low rates of constitutional symptoms were reported in this physician-based survey with concentration problems, fatigue and itching being the main PV-related symptoms. Phlebotomy and hydroxyurea were the main cytoreductive measures for hematocrit control. The majority of patients were responsive (67.8 %) and tolerant (77.3 %) to hydroxyurea therapy. Interferon and JAK inhibitor therapy were used in <10 % of patients, respectively. Overall, leukocytosis, thrombocytosis and hematocrit could be effectively controlled by any therapy applied. Lack of efficacy was reported on reduction of constitutional symptoms and splenomegaly.

Conclusions

The patient population investigated was older than participants in published large multicenter trials. The majority of patients were categorized as 'high risk.' Age was the main risk factor. Molecular status was unavailable in the majority of patients diagnosed prior to 2008. The physician-based survey reported on significantly lower rates of constitutional symptoms than patient-based surveys in the literature. Consistent with previously published reports, hydroxyurea is the main agent used for PV therapy in an outpatient setting resulting in efficient control of hematopoietic parameters. Constitutional symptoms and splenomegaly, however, may not be reduced efficiently, which could be improved by the use of JAK inhibitor treatment for high-risk patients in the future.

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Prognostic significance of pattern and burden of metastatic disease in patients with stage 4 neuroblastoma: A study from the International Neuroblastoma Risk Group database

Publication date: September 2016
Source:European Journal of Cancer, Volume 65
Author(s): Daniel A. Morgenstern, Wendy B. London, Derek Stephens, Samuel L. Volchenboum, Thorsten Simon, Akira Nakagawara, Hiroyuki Shimada, Gudrun Schleiermacher, Katherine K. Matthay, Susan L. Cohn, Andrew D.J. Pearson, Meredith S. Irwin
Neuroblastoma is a childhood cancer with remarkably divergent tumour behaviour and the presence of metastatic disease is a powerful predictor of adverse outcome. However, the importance of the involvement of specific metastatic sites or overall metastatic burden in determining outcome has not been fully explored. We analysed data from the International Neuroblastoma Risk Group database for 2250 patients with stage 4 disease treated from 1990 to 2002. Metastatic burden was assessed using a 'metastatic site index' (MSI), a score based on the number of metastatic systems involved. Overall, involvement of bone marrow, bone, lung, central nervous system, or other sites was associated with worse outcome. For patients aged ≥18 months, involvement of liver had the greatest impact on outcome and was associated with tumour MYCN amplification and adrenal primary and lung metastases. Increased MSI was associated with worse outcome and higher baseline ferritin/lactate dehydrogenase. We explored the impact of initial treatment approach on these associations. Limiting the analysis to patients allocated to protocols including stem cell transplant (SCT), there was no longer an association of outcome with metastatic involvement of any individual system or increasing MSI. Thus, treatment escalation with SCT (and the addition of differentiating agents to maintenance therapy) appears to have provided maximal benefit to patients with greatest metastatic disease burden. These findings underscore the importance of examining prognostic factors in the context of specific treatments since the addition of new therapies may change or even negate the predictive impact of a particular variable.



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A Randomized Controlled Study to Observe the Efficacy of External Treatment With a Traditional Chinese Medicine Herbal Ointment on Malignant Plural Effusion: Outcome Report and Design Review

Background. Malignant pleural effusion (MPE) is a common complication in most malignancies. Despite its frequent occurrence, current knowledge of MPE remains limited and the effect of the management is still unsatisfying. Traditional Chinese medicine (TCM) external treatment has unique advantages, such as quicker efficacy and fewer side effects. Objective. To observe the effects and safety of Kang'ai Xiaoshui ointment (TCM herbal ointment) in MPE. Design. This was a placebo-controlled double-blinded randomized study. A total of 80 patients were enrolled, of which 72 were randomized to receive Kang'ai Xiaoshui ointment or placebo at an allocation ratio of 1:1. Kang'ai Xiaoshui ointment or placebo was applied on the thorax wall for 8 hours daily. The intervention lasted 2 weeks. Kang'ai Xiaoshui ointment consisted of Astragalus membranaces (黄), Semen pharbitidis (牛子), Cassia twig (桂枝), Pericarpium arecae (大腹皮), Curcuma zedoary (术), Borneol (冰片), and other substances. In both groups, diuresis and drainages were used as needed. Outcomes covered the quantity of pleural effusion evaluation, TCM Symptom Scale, Karnofsky Performance Scale, and safety indicators such as routine blood test, blood biochemistry test, and response table of skin irritation. Results. Of 72 patients randomized to receive Kang'ai Xiaoshui ointment or placebo along with symptomatic treatment, the response rate was documented as 42.4% for the treatment group and 25.0% for the placebo group (P = .138). As for the TCM symptom scale, the treatment group showed improvement in chest distress (P = .003), fullness and distention (P = .042), shortness of breath (P < .001), no statistical significance in palpitation (P = .237), and pain (P = .063), whereas the placebo group did not show statistical significance in any of the 5 symptoms. Major adverse events related to the treatment, mainly skin irritation, were distributed equally. Conclusions. Kang'ai Xiaoshui ointment showed a potential of reducing MPE, and it could alleviate symptoms of dyspnea. Thus, it may be appropriate as a supplementary intervention for MPE. There were some flaws in the study design. A larger scale and better designed trial is advocated.

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Randomised trial on treatment of vaginal intraepithelial neoplasia – imiquimod, laser vaporisation, and expectant management

Abstract

Vaginal intraepithelial neoplasia (VAIN) is associated with human papillomavirus (HPV) infection. The most common treatment modality is laser vaporisation, but recurrencies are common. Imiquimod is an immune response modulator which is used for the treatment of external condylomas and other HPV-related genital neoplasias. The aim of the study was to evaluate the efficacy and tolerability of vaginally administered imiquimod in comparison with laser vaporisation and expectant management of high grade VAIN. This proof of principle pilot study was a prospective 16-week randomised trial. We enrolled 30 patients with histologically confirmed VAIN 2 or 3 into three study arms: vaginally administered imiquimod, laser vaporisation, and expectant management. Follow-up colposcopy visits included high-risk human papillomavirus (hrHPV) testing, cytology, and punch biopsies. At baseline 77% (n=20/26) of the patients were hrHPV positive. HPV clearance was significantly higher in the imiquimod arm (63%, n=5/8) than in the laser arm (11%, n=1/9) (p=0.05) or in the expectant management arm (17%, n=1/6) (p=0.138). At baseline 25 patients (83%) had VAIN 2 and five (17%) had VAIN 3. None of the lesions progressed during the follow-up. Histological regression (≤ VAIN 1) was observed in 80% (n= 8/10) of patients in the imiquimod arm, 100% (n=10/10) of the laser arm (p=0.474) and 67% (n=6/9) of the expectant management arm (p=0.628). Vaginal imiquimod appears to be as effective as laser treatment in high grade VAIN. This article is protected by copyright. All rights reserved.

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Preclinical evaluation of near-infrared (NIR) fluorescently labeled Cetuximab as a potential tool for fluorescence-guided surgery

Abstract

The high rate of recurrence in patients with pancreatic ductal adenocarcinoma (PDAC) could be reduced by supporting the surgeons in discriminating healthy from diseased tissues with intraoperative fluorescence-guidance. Here, we studied the suitability of Cetuximab, a therapeutic monoclonal antibody targeting the human epidermal growth factor receptor (EGFR), NIR fluorescently labeled as a new tool for fluorescence-guided surgery (FGS). Distribution and binding of systemically injected Cetuximab Alexa Fluor 647 conjugate (Cetux-Alexa-647) and the co-injected control human IgG Alexa Fluor 750 conjugate (hIgG-Alexa-750) was studied over 48h by near-infrared fluorescence (NIRF) imaging in mice bearing human orthotopic AsPC-1 and MIA PaCa-2 PDAC tumors. Cetux-Alexa-647, but not the control hIgG-Alexa-750 fluorescence, was specifically detected in vivo in both primary pancreatic tumors and in metastases of AsPC-1 tumors as small as 1 mm, with maximum fluorescence intensities at 24 h. Lifetime (LT) analysis and NIRF microscopy of tumor sections confirmed the binding specificity of Cetux-Alexa-647 to PDAC cells. Comparable results were obtained with Cetuximab conjugated to Alexa Fluor 750 dye (Cetux-Alexa-750). Fluorescence-guided dissection, performed 24 h after injection of Cetuximab conjugated to IRDye 800CW (Cetux-800CW), enabled a real time delineation of AsPC-1 tumor margins, and small metastases. Odyssey scans revealed that only the vital part of the tumor, but not the necrotic part was stained with Cetux-800CW. NIR fluorescently labeled Cetuximab may be a promising tool that can be applied for FGS to visualize tumor margins and metastatic sites in order to allow a precise surgical resection. This article is protected by copyright. All rights reserved.

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Relationship between tumor biomarkers and efficacy in TH3RESA, a phase III study of trastuzumab emtansine (T-DM1) versus treatment of physician's choice in previously treated HER2-positive advanced breast cancer

ABSTRACT

In the phase III TH3RESA study (NCT01419197), 602 patients with HER2-positive advanced breast cancer who received prior taxane therapy and ≥2 HER2-directed regimens, including trastuzumab and lapatinib (advanced setting), were randomized to trastuzumab emtansine (T-DM1) or treatment of physician's choice (TPC). A statistically significant progression-free survival (PFS) benefit favoring T-DM1 was demonstrated. Here we examine the relationship between HER2-related biomarkers and PFS in an exploratory analysis. Biomarkers assessed included HER2 (n=505) and HER3 (n=505) mRNA expression, PIK3CA mutation status (n=410), and PTEN protein expression (n=358). For biomarkers with continuous data (HER2, HER3, PTEN), subgroups were defined using median values (>median and ≤median). For all biomarker subgroups, median PFS was longer with T-DM1 versus TPC. The PFS benefit favoring T-DM1 versus TPC was numerically greater in the HER2 mRNA >median subgroup (7.2 vs. 3.4 months; unstratified hazard ratio [HR], 0.40; 95% CI, 0.28–0.59; p<0.0001) versus ≤median subgroup (5.5 vs. 3.9 months; HR, 0.68; 95% CI, 0.49–0.92; p=0.0131). The PFS benefit with T-DM1 was similar among HER3, PIK3CA, and PTEN subgroups. Consistent with other reports, benefit was seen with T-DM1 regardless of PIK3CA mutation status. In a multivariate analysis including an interaction term (treatment group by log2-transformed HER2 mRNA), patients with higher HER2 mRNA levels benefited more from receiving T-DM1 (HR, 0.84; 95% CI, 0.75–0.94; interaction p-value=0.0027). In summary, T-DM1 prolonged median PFS in all biomarker subgroups analyzed, including activating PIK3CA mutations, with numerically greater benefit in patients with tumors expressing HER2 mRNA >median versus ≤median. This article is protected by copyright. All rights reserved.

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Prostate-specific antigen testing for prostate cancer: Depleting a limited pool of susceptible individuals?

Abstract

After the introduction of the prostate specific antigen (PSA) test in the 1980s, a sharp increase in the incidence rate of prostate cancer was seen in the United States. The age-specific incidence patterns exhibited remarkable shifts to younger ages, and declining rates were observed at old ages. Similar trends were seen in Norway. We investigate whether these features could, in combination with PSA testing, be explained by a varying degree of susceptibility to prostate cancer in the populations. We analyzed incidence data from the United States' Surveillance, Epidemiology, and End Results program for 1973–2010, comprising 511,027 prostate cancers in men ≥40 years old, and Norwegian national incidence data for 1953–2011, comprising 113,837 prostate cancers in men ≥50 years old. We developed a frailty model where only a proportion of the population could develop prostate cancer, and where the increased risk of diagnosis due to the massive use of PSA testing was modelled by encompassing this heterogeneity in risk. The frailty model fits the observed data well, and captures the changing age-specific incidence patterns across birth cohorts. The susceptible proportion of men is \(39.9\,\%\,\left( {95\,\%\,{\text{CI}}\, 38.2, 41.6\,\% } \right)\) in the United States and \(30.4\,\%\, \left( {95\,\%\, {\text{CI}} \,28.9, 32.0\,\% } \right)\) in Norway. Cumulative incidence rates at old age are unchanged across birth cohort exposed to PSA testing at younger and younger ages. The peaking cohort-specific age-incidence curves of prostate cancer may be explained by the underlying heterogeneity in prostate cancer risk. The introduction of the PSA test has led to a larger number of diagnosed men. However, no more cases are being diagnosed in total in birth cohorts exposed to the PSA era at younger and younger ages, even though they are diagnosed at younger ages. Together with the earlier peak in the age-incidence curves for younger cohorts, and the strong familial association of the cancer, this constitutes convincing evidence that the PSA test has led to a higher proportion, and an earlier timing, of diagnoses in a limited pool of susceptible individuals.

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Dynamic contrast enhanced CT in nodule characterization: How we review and report

Abstract

Incidental indeterminate solitary pulmonary nodules (SPN) that measure less than 3 cm in size are an increasingly common finding on computed tomography (CT) worldwide. Once identified there are a number of imaging strategies that can be performed to help with nodule characterization. These include interval CT, dynamic contrast enhanced computed tomography (DCE-CT), ¹⁸F-fluorodeoxyglucose positron emission tomography-computed tomography (¹⁸F-FDG-PET-CT). To date the most cost effective and efficient non-invasive test or combination of tests for optimal nodule characterization has yet to be determined.

DCE-CT is a functional test that involves the acquisition of a dynamic series of images of a nodule before and following the administration of intravenous iodinated contrast medium. This article provides an overview of the current indications and limitations of DCE- CT in nodule characterization and a systematic approach to how to perform, analyse and interpret a DCE-CT scan.

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Disorganized Steroidogenesis in Adrenocortical Carcinoma, a Case Study

Abstract

Most adrenocortical carcinomas (ACCs) produce excessive amounts of steroid hormones including aldosterone, cortisol, and steroid precursors. However, aldosterone- and cortisol-producing cells in ACCs have not yet been immunohistochemically described. We present a case of ACC causing mild primary aldosteronism and subclinical Cushing's syndrome. Removal of the tumor cured both conditions. In order to examine the expression patterns of the steroidogenic enzymes responsible for adrenocortical hormone production, 10 tumor portions were immunohistochemically analyzed for aldosterone synthase (CYP11B2), 11β-hydroxylase (CYP11B1, cortisol-synthesizing enzyme), 3β-hydroxysteroid dehydrogenase (3βHSD, upstream enzyme for both CYP11B2 and CYP11B1), and 17α-hydroxylase/C17-20 lyase (CYP17, upstream enzyme for CYP11B1, but not for CYP11B1). CYP11B2, CYP11B1, and 3βHSD were expressed sporadically, and their expression patterns varied significantly among the different tumor portions examined. The expression of these enzymes was random and not associated with each other. CYP17 was expressed throughout the tumor, even in CYP11B2-positive cells. Small tumor cell populations were aldosterone- or cortisol-producing cells, as judged by 3βHSD coinciding with either CYP11B2 or CYP11B1, respectively. These results suggest that the tumor produced limited amounts of aldosterone and cortisol due to the lack of the coordinated expression of steroidogenic enzymes, which led to mild clinical expression in this case. We delineated the expression patterns of steroidogenic enzymes in ACC. The coordinated expression of steroidogenic enzymes in normal and adenoma cells was disturbed in ACC cells, resulting in the inefficient production of steroid hormones in relation to the large tumor volume.

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Principles of Healthful Eating

Abstract

This paper provides a broad and clinically relevant overview of the principles of healthful eating via an in-depth discussion of the three major macronutrients, carbohydrates, protein, and fat, and their role in health and disease. The health benefits of specific key food groups including whole grains, fruits, and vegetables are presented along with up to date information on more controversial foods including eggs, red meat, and processed red meat. In addition, the latest findings and recommendations on key micronutrients including sodium, calcium, and vitamin D are presented along with a brief discussion of the emerging importance of the microbiome in health and disease and the impact of diet on the commensal bacteria within the gastrointestinal tract.

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Multi-omics landscapes of colorectal cancer subtypes discriminated by an individualized prognostic signature for 5-fluorouracil-based chemotherapy

Multi-omics landscapes of colorectal cancer subtypes discriminated by an individualized prognostic signature for 5-fluorouracil-based chemotherapy

Oncogenesis 5, e242 (July 2016). doi:10.1038/oncsis.2016.51

Authors: M Tong, W Zheng, H Li, X Li, L Ao, Y Shen, Q Liang, J Li, G Hong, H Yan, H Cai, M Li, Q Guan & Z Guo

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Activation of the Met kinase confers acquired drug resistance in FGFR-targeted lung cancer therapy

Activation of the Met kinase confers acquired drug resistance in FGFR-targeted lung cancer therapy

Oncogenesis 5, e241 (July 2016). doi:10.1038/oncsis.2016.48

Authors: S-M Kim, H Kim, M R Yun, H N Kang, K-H Pyo, H J Park, J M Lee, H M Choi, P Ellinghaus, M Ocker, S Paik, H R Kim & B C Cho

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A single-center experience with undifferentiated embryonal sarcoma of the liver

Abstract

Undifferentiated embryonal sarcoma of the liver (UESL) is a rare aggressive mesenchymal pediatric tumor. Previously, reported outcomes have been very poor. Here, we report a single-center experience of five patients with UESL treated with upfront gross total resection and adjuvant chemotherapy. We have a median follow-up of 8 years with a range from 5 to 19 years with 100% event-free survival.

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Rothia mucilaginosa infection in a child with acute lymphoblastic leukemia

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Otologic manifestations of Fanconi anemia and other inherited bone marrow failure syndromes

Abstract

Background

The inherited bone marrow failure syndromes (IBMFSs) are diverse disorders with syndrome-specific features; their otologic and audiologic manifestations have not been well described. Our objective was to characterize these in patients with Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond–Blackfan anemia (DBA), and Shwachman–Diamond syndrome (SDS), and to determine the association between physical findings and hearing loss.

Methods

Patients with an IBMFS underwent comprehensive clinical and laboratory evaluations and testing for syndrome-specific gene mutations. Hearing loss was measured by pure tone audiometry and otologic abnormalities by otomicroscopy.

Results

Patients included 33 with FA, 37 with DC, 32 with DBA, and nine with SDS. Hearing loss was most frequent in patients with FA (45%) and DBA (14%). The most common type of hearing loss in FA was conductive (65%). Absent or hypoplastic radius, noted in 21% of the patients with FA, was associated with hearing loss in all cases. Otomicroscopy was abnormal in 66% of patients with FA. Characteristic ear abnormalities included small tympanic membrane (66%), malformed malleus (57%), aberrant tympanic bony island (48%), narrow external auditory canal (EAC) (32%), and abnormal course of chorda tympani (34%). Ear malformations were almost always associated with hearing loss. Hearing loss was rare in patients with DC and SDS.

Conclusions

FA is the major IBMFS with associated hearing loss, which is most commonly conductive. Radial hypoplasia or aplasia and characteristic congenital ear malformations are associated with hearing loss in patients with FA. Recognition of these syndrome-specific abnormalities should lead to earlier management of hearing loss.

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Patient/parent perspectives on genomic tumor profiling of pediatric solid tumors: The Individualized Cancer Therapy (iCat) experience

Abstract

Background

Genomic tumor profiling (GTP) plays an important role in the care of many adult cancer patients. Its role in pediatric oncology is still evolving, with only a subset of patients currently expected to receive clinically significant results. Little is known about perspectives of pediatric oncology patients/parents on GTP.

Procedure

We surveyed individuals who previously underwent GTP through the iCat (Individualized Cancer Therapy) pilot study of molecular profiling in children with relapsed, refractory, and high-risk solid tumors at four pediatric cancer centers. Following return of profiling results, a cross-sectional survey was offered to the patient, if he or she was 18 years or older at enrollment, or parent, if he or she was under 18 years of age. Forty-five surveys (85% response) were completed.

Results

Eighty-nine percent (39/44) of respondents reported hoping participation would help find cures for future patients, while 59% (26/44) hoped it would increase their/their child's chance of cure. Most had few concerns about GTP, but 12% (5/43) worried they would learn their/their child's cancer was less treatable or more aggressive than previously thought. Sixty-four percent (29/45) reported feeling their participation had helped others and 44% (20/45) felt they had helped themselves/their own child, despite only one substudy subject receiving targeted therapy matched to GTP findings. Fifty-four percent (21/39) wished to receive all available profiling data, including findings unrelated to cancer and of unclear significance.

Conclusions

Participants in pediatric GTP research perceive benefits of GTP to themselves and others, but expectations of personal benefits of GTP may exceed actual positive impact. These issues warrant consideration during consent discussions about GTP research participation.

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Biochemical composition of malignant ascites determines high aggressiveness of undifferentiated ovarian tumors

Abstract

Although undifferentiated tumors are the most lethal among all ovarian cancer histotypes, the exact reasons for this situation are unclear. This report was aimed at investigating whether the high aggressiveness of undifferentiated ovarian cancer may be associated with a biochemical composition of malignant ascites accumulating in the peritoneal cavity. We analyzed ascites from patients with undifferentiated, high-grade serous, endometrioid and clear-cell ovarian cancers, and from non-cancerous patients with respect to a group of soluble agents involved in cancer cell progression. Moreover, the effect of these fluids on proliferation and migration of ovarian cancer cells (A2780, OVCAR-3 and SKOV-3) was evaluated. The study showed that the level of all tested proteins in malignant ascites was higher than in the benign fluids. Concentration of 9/11 agents (CCL2, CXCL1, CXCL5, CXCL8, CXCL12, HGF, PAI-1, TGF-β1 and VEGF) was the greatest in the fluids from undifferentiated cancer, while the level of remaining 2 (IL-6 and uPA) was the highest in ascites from serous carcinoma. Proliferation of cancer cells was the most effective when they were subjected to ascites from patients with undifferentiated and serous cancer, whereas the migration was the highest in the case of undifferentiated tumors. Our findings indicate that the aggressiveness of undifferentiated ovarian tumors may be associated with the composition of malignant ascites, in particular the concentration of specific proinflammatory, cancer-promoting agents.

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Randomized, Double-Blind, Placebo Controlled Study of Methylphenidate for the Treatment of Depression in SSRI-Treated Cancer Patients Receiving Palliative Care

Abstract

Objective

To determine the effectiveness of methylphenidate for depression treatment in advanced cancer patients.

Methods

An 18-day randomized, double-blind, placebo-controlled clinical trial of methylphenidate for treatment of depression in selective serotonin reuptake inhibitor (SSRI)-treated patients with advanced cancer in hospice or receiving palliative care. The primary outcome was depression remission, defined as a ≥50% reduction in score on the Montgomery-Asberg Depression Rating Scale.

Results

Among 47 enrolled participants, 35 were randomized. At study day 18, 85% of the methylphenidate and 60% of the placebo group were in depression remission (p = 0.22). Mean time to depression remission was 10.3 days [standard error (SE) 1.8] in the methylphenidate and 8.1 (SE 1.3) in the placebo group (p = 0.48). The mean baseline score for the Hospital Anxiety and Depression Scale (HADS) was 10.4 in each group and decreased by 3.6 (SE 1.1) in the methylphenidate and 2.3 (SE 1.2) in the placebo group (p = 0.51) by day 18. Once in remission, 1 methylphenidate and 5 placebo participants relapsed to depression (p = 0.18). There was no difference in mortality between the groups during the trial. Trial results were limited by small sample size attributed to difficulties in recruiting terminally ill patients.

Conclusions

This trial failed to demonstrate that methylphenidate treatment in SSRI-treated patients had a significant effect on depression remission in advanced cancer patients. This study underscores the difficulties in conducting trials for symptom management in patients with shortened life expectancy.

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Prostate-specific antigen testing for prostate cancer: Depleting a limited pool of susceptible individuals?

Abstract

After the introduction of the prostate specific antigen (PSA) test in the 1980s, a sharp increase in the incidence rate of prostate cancer was seen in the United States. The age-specific incidence patterns exhibited remarkable shifts to younger ages, and declining rates were observed at old ages. Similar trends were seen in Norway. We investigate whether these features could, in combination with PSA testing, be explained by a varying degree of susceptibility to prostate cancer in the populations. We analyzed incidence data from the United States' Surveillance, Epidemiology, and End Results program for 1973–2010, comprising 511,027 prostate cancers in men ≥40 years old, and Norwegian national incidence data for 1953–2011, comprising 113,837 prostate cancers in men ≥50 years old. We developed a frailty model where only a proportion of the population could develop prostate cancer, and where the increased risk of diagnosis due to the massive use of PSA testing was modelled by encompassing this heterogeneity in risk. The frailty model fits the observed data well, and captures the changing age-specific incidence patterns across birth cohorts. The susceptible proportion of men is \(39.9\,\%\,\left( {95\,\%\,{\text{CI}}\, 38.2, 41.6\,\% } \right)\) in the United States and \(30.4\,\%\, \left( {95\,\%\, {\text{CI}} \,28.9, 32.0\,\% } \right)\) in Norway. Cumulative incidence rates at old age are unchanged across birth cohort exposed to PSA testing at younger and younger ages. The peaking cohort-specific age-incidence curves of prostate cancer may be explained by the underlying heterogeneity in prostate cancer risk. The introduction of the PSA test has led to a larger number of diagnosed men. However, no more cases are being diagnosed in total in birth cohorts exposed to the PSA era at younger and younger ages, even though they are diagnosed at younger ages. Together with the earlier peak in the age-incidence curves for younger cohorts, and the strong familial association of the cancer, this constitutes convincing evidence that the PSA test has led to a higher proportion, and an earlier timing, of diagnoses in a limited pool of susceptible individuals.

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Cerebral malperfusion in acute aortic dissection

Abstract

Cerebral malperfusion in association with acute type A aortic dissection is uncommon but can have a considerable effect on the outcome of treatment. Successful treatment requires the individual and effective removal of each of the factors associated with malperfusion. In addition to the conventional surgical procedures, endovascular treatment has become an option for restoring perfusion. However, artificial perfusion and/or surgical procedures can lead to new malperfusion, which is not necessarily apparent to surgeons and which is difficult to predict. Thus, a number of modalities need to be applied to monitoring the current status of perfusion to enable timely treatment. Since each of the diagnostic modalities has its merits and demerits, one should use them effectively while being mindful of the pitfalls. In addition, a delay in the diagnosis in the pre-hospital stage is an important determinant of the surgical outcomes of aortic dissection. Portable echocardiography, which has been recently developed, may be useful for improving this situation. However, an early diagnosis largely depends on the physician's awareness and basic echocardiography skills. Surgeons should make general physicians aware of this message.

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Role of fibronectin in the process of human intestinal cell disruption during E. histolytica infection

Abstract

Entamoeba histolytica is a protozoan that causes amoebiasis in humans which in extreme cases can result in death. One of the virulence factors of E. histolytica is cysteine proteinase which is involved with disruption, inflammation, and apoptosis of the intestinal cell layers. This disruption facilitates the amoeba's penetration into the vascular system and hence to metastasize into other organs. Cysteine proteinase blocks activity of several human proteins in the extracellular matrix, such as mucin-2, collagen, fibronectin, and laminin. Inhibition of several protein activities are predicted to lead the disruption of intestinal mucus, but the detailed mechanism is still unclear. We examined the mechanism using topology networks and functional analysis and the result showed links to 765 proteins, of which fibronectin was predominant in the network. Fibronectin interacts with ubiquitin conjugate, insulin-like factor binding protein-3, and integrin alpha chain-2 which play pivotal roles in maintaining cell cycle, survival, and apoptosis. Therefore, inhibition of the protein results in intestinal cells losing the ability to maintain homeostasis mechanism by which the disruption of intestinal cell occurs.

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Acute renal failure by use of dipyrone in Cavia porcellus

Abstract

Renal failure is a condition that occurs when one or more functions of the kidneys are changed and in guinea pig (Cavia porcellus) its occurrence is uncommon but always lethal. This paper reports the occurrence of acute renal failure in a patient mistakenly treated with dipyrone for 5 days in a veterinary hospital of UNOESC/Xanxerê-SC, presenting apathy, anorexia and hematuria diagnosed through laboratory tests. The use of dipyrone generated an eminent intoxication condition and the specific knowledge of therapy and familiarity with exotic animal species is extremely important to avoid cases of iatrogenic intoxication.

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Developing Sustainable Cancer Education Programs: Training Public Health Students to Deliver Cancer 101 in Puerto Rico

Abstract

The use of promotores to educate Hispanic communities about different health topics has been proven successful, albeit with limitations in program sustainability. The goal of this study was to develop a sustainable train-the-trainer model to train graduate public health (PH) students to disseminate cancer education among communities in Puerto Rico (PR). Graduate students (n = 32) from Ponce Health Sciences University's (PHSU) PH program participated in a 2-day Cáncer 101 training, where they learned how to deliver nine cancer modules to the community. Cancer knowledge was assessed before and after the training via 54 items measuring discussed concepts. Participants also assessed the training's effectiveness by completing a training evaluation informed by social cognitive theory (SCT) constructs of self-efficacy, outcome expectations, facilitation, and observational learning. Participants were mainly female (78.1 %), 26.7 ± 3.9 years old, and enrolled in a Masters-level program (81.3 %). Participants reported an average 11.38-point increase in cancer knowledge after attending the training [t(31) = 14.88, p < .001]. Participants also evaluated the training favorably upon completion, reporting satisfactory comments in the open-ended responses and high scores on measured SCT constructs. The Cáncer 101 training program effectively prepared students to deliver cancer education to local communities. Training graduate PH students to educate communities about health issues is an innovative, and potentially sustainable, way to reach underserved populations.

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Low expressions of ASS1 and OTC in glioblastoma suggest the potential clinical use of recombinant human arginase (rhArg)

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Low expressions of ASS1 and OTC in glioblastoma suggest the potential clinical use of recombinant human arginase (rhArg)

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Pushing boundaries - culture sensitive care in oncology and palliative care: A qualitative study

Abstract

Objective

In increasingly globalized societies patient-centred cancer care requires culture-sensitive approaches in order to ensure patients wellbeing. While migrant patients' needs are frequently reported in the literature, staff members' perception of work with migrant patients, associated challenges or individual work approaches are largely unknown. This study addresses this research gap through qualitative exploration of experiences of multi-cultural healthcare professionals in supportive oncology and palliative care, working with patients from different cultural backgrounds. This study aims to understand staff experience of the impact of culture on cancer care.

Methods

This study was conducted at the Medical University Vienna, including staff from different settings of oncology and palliative care, in different professional positions and with a range of individual migration backgrounds. Semi-structured interviews were conducted with 21 staff members working with patients from different cultural backgrounds. Interviews explored views on the impact of culture on care, were audio-taped, transcribed and analysed using a rigorous method of thematic analysis, enhanced with grounded theory techniques.

Results

Interviews revealed four key topics: culture-specific differences, assumed reasons for differences, consequences of multi-cultural care, and tools for culture-sensitive care. Strategies to better deal with migrant patients and their families were suggested to improve work satisfaction amongst staff.

Conclusions

This study identifies relevant staff challenges in work with migrant patients. Concrete suggestions for improvement include measures on an organizational level, team level, and personal tools. The suggested measures are applicable to improve work satisfaction and culture-sensitive care not only cancer care, but also in other areas of medicine.

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Cancers, Vol. 8, Pages 69: Wnt Lipidation and Modifiers in Intestinal Carcinogenesis and Cancer

The wingless (Wnt) signaling is suggested as a fundamental hierarchical pathway in regulation of proliferation and differentiation of cells. The Wnt ligands are small proteins of about 40 kDa essentially for regulation and initiation of the Wnt activity. They are secreted proteins requiring acylation for activity in the Wnt signaling cascade and for functional interactivity with transmembrane proteins. Dual lipidation is important for posttranslational activation of the overwhelming number of Wnt proteins and is probably involved in their spatial distribution. The intestinal mucosa, where Wnt signaling is essential in configuration and maintenance, is an established model to study Wnt proteins and their role in carcinogenesis and cancer. The intestinal crypt-villus/crypt-plateau axis, a cellular system with self-renewal, proliferation, and differentiation, is tightly coordinated by a Wnt gradient. In the review, some attention is given to Wnt3, Wnt3A, and Wnt2B as important members of the Wnt family to address the role of lipidation and modifiers of Wnt proteins in intestinal carcinogenesis. Wnt3 is an important player in establishing the Wnt gradient in intestinal crypts and is mainly produced by Paneth cells. Wnt2B is characterized as a mitochondrial protein and shuttles between mitochondria and the nucleus. Porcupine and ACSL5, a long-chain fatty acid activating enzyme, are introduced as modifiers of Wnts and as interesting strategy to targeting Wnt-driven carcinogenesis.

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Developing Sustainable Cancer Education Programs: Training Public Health Students to Deliver Cancer 101 in Puerto Rico

Abstract

The use of promotores to educate Hispanic communities about different health topics has been proven successful, albeit with limitations in program sustainability. The goal of this study was to develop a sustainable train-the-trainer model to train graduate public health (PH) students to disseminate cancer education among communities in Puerto Rico (PR). Graduate students (n = 32) from Ponce Health Sciences University's (PHSU) PH program participated in a 2-day Cáncer 101 training, where they learned how to deliver nine cancer modules to the community. Cancer knowledge was assessed before and after the training via 54 items measuring discussed concepts. Participants also assessed the training's effectiveness by completing a training evaluation informed by social cognitive theory (SCT) constructs of self-efficacy, outcome expectations, facilitation, and observational learning. Participants were mainly female (78.1 %), 26.7 ± 3.9 years old, and enrolled in a Masters-level program (81.3 %). Participants reported an average 11.38-point increase in cancer knowledge after attending the training [t(31) = 14.88, p < .001]. Participants also evaluated the training favorably upon completion, reporting satisfactory comments in the open-ended responses and high scores on measured SCT constructs. The Cáncer 101 training program effectively prepared students to deliver cancer education to local communities. Training graduate PH students to educate communities about health issues is an innovative, and potentially sustainable, way to reach underserved populations.

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