Cancer by Sfakianakis Alexandros: 12/11/17

Δευτέρα 11 Δεκεμβρίου 2017

Effects of physical exercise on markers of inflammation in breast cancer patients during adjuvant chemotherapy

Abstract

Purpose

Exercise has been shown to reduce fatigue during cancer treatment. Hypothesized mechanisms include inflammatory pathways. Therefore, we investigated effects of exercise on markers of inflammation in breast cancer patients during adjuvant chemotherapy.

Methods

We pooled data from two randomized controlled exercise intervention trials with breast cancer patients during adjuvant chemotherapy (n = 130), which had previously shown beneficial effects of exercise on fatigue. Exercise comprised a 12-week resistance training (BEATE study) or an 18-week combined resistance and aerobic training (PACT study). Serum IL-6, IL-1ra, and the IL-6/IL-1ra ratio were quantified at baseline, mid-intervention, post-intervention, and 6–9 months post-baseline.

Results

Mixed effect models showed significant increases in IL-6 and IL-6/IL-1ra ratio during chemotherapy and decreases afterwards. Differences between exercise and control group were not significant at any time point. Changes in total cancer-related fatigue were significantly correlated with changes in IL-6/IL-1ra ratio (partial correlation r = 0.23) and IL-6 (r = 0.21), and changes in physical cancer-related fatigue with changes in IL-6/IL-1ra ratio (r = 0.21).

Conclusions

Changes in fatigue were slightly correlated with changes in inflammatory markers, and there was a strong inflammatory response to adjuvant chemotherapy. The supervised exercise training did not counteract this increase in inflammation, suggesting that beneficial effects of exercise on fatigue during adjuvant chemotherapy for breast cancer are not essentially mediated by IL-6, IL-1ra, or the IL-6/IL-1ra ratio.

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Electroconvulsive therapy for manic state with mixed and psychotic features in a teenager with bipolar disorder and comorbid episodic obsessive–compulsive disorder: a case report

Comorbidity of bipolar disorder and obsessive–compulsive disorder is common in adolescence. Obsessive–compulsive disorder symptoms may be episodic and secondary to alterations in mood, and display specific fea...

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Worse survival after breast cancer in women with anorexia nervosa

Abstract

Purpose

A history of anorexia nervosa has been associated with a reduced risk of developing breast cancer. We investigated survival after breast cancer among women with a prior anorexia nervosa diagnosis compared with women in a population comparison group.

Methods

This register-based study included combined data from Sweden, Denmark and Finland. A total of 76 and 1462 breast cancer cases identified among 22,654 women with anorexia nervosa and 224,619 women in a population comparison group, respectively, were included in the study. Hazard ratios (HR) for overall and breast cancer-specific mortality after breast cancer diagnosis were estimated using Cox regression. Cause of death was available only for Swedish and Danish women; therefore, the analysis on breast cancer-specific mortality was restricted to these women.

Results

We observed 23 deaths after breast cancer among anorexia nervosa patients and 247 among population comparisons. The overall mortality after the breast cancer diagnosis was increased in women with a history of anorexia nervosa compared with population comparisons (HR 2.5, 95% CI 1.6–3.9) after adjustment for age, period and extent of disease. Results were similar for overall (HR 2.3, 95% CI 1.4–3.6) and breast cancer-specific mortality (HR 2.1, 95% CI 1.3–3.6) among Swedish and Danish women.

Conclusions

We found that female breast cancer patients with a prior diagnosis of anorexia nervosa have a worse survival compared with other breast cancer patients.

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Placental abruption leading to hysterectomy

A 32-year-old multigravid patient at 21 weeks gestation presents with major concealed placental abruption and subsequent fetal demise. During an eventually failed misoprostol regime aiming for vaginal delivery she develops severe disseminated intravascular coagulopathy. Subsequent hysterotomy reveals Couvelaire uterus with major haemorrhage and requires subtotal hysterectomy for haemostasis. This case highlights the severity of the systemic response to abruption and fetal demise in utero and the multifactorial nature of its management.

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Pathology of retroperitoneal sarcomas: A brief review

Sarcomas represent a highly heterogeneous group of tumors as reflected in the significant overlap between their histologic phenotypes between the different types, posing diagnostic challenges for the pathologist. Definitive tumor classification is increasingly important because of prognostication and emergence of targeted therapies for some of the sarcoma types. In this review, we highlight pertinent pathologic and molecular aspects of sarcomas common in the retroperitoneum, relevant to the surgical oncologist.

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Neoadjuvant radiotherapy combined with capecitabine and sorafenib in patients with advanced KRAS-mutated rectal cancer: A phase I/II trial (SAKK 41/08)

Publication date: January 2018
Source:European Journal of Cancer, Volume 89
Author(s): Roger von Moos, Dieter Koeberle, Sabina Schacher, Stefanie Hayoz, Ralph C. Winterhalder, Arnaud Roth, György Bodoky, Panagiotis Samaras, Martin D. Berger, Daniel Rauch, Piercarlo Saletti, Ludwig Plasswilm, Daniel Zwahlen, Urs R. Meier, Pu Yan, Paola Izzo, Dirk Klingbiel, Daniela Bärtschi, Kathrin Zaugg
BackgroundKRAS mutation occurs in ∼40% of locally advanced rectal cancers (LARCs). The multitarget tyrosine kinase inhibitor sorafenib has radiosensitising effects and might improve outcomes for standard preoperative chemoradiotherapy in patients with KRAS-mutated LARC.MethodsAdult patients with KRAS-mutated T3/4 and/or N1/2M0 LARC were included in this phase I/II study. The phase I dose-escalation study of capecitabine plus sorafenib and radiotherapy was followed by a phase II study assessing efficacy and safety. Primary end-points were to: establish the maximum tolerated dose of the regimen in phase I; determine the pathologic complete response (pCR) rate in phase II defined as Dworak regression grade 3 and 4.ResultsFifty-four patients were treated at 18 centres in Switzerland and Hungary; 40 patients were included in the single-arm phase II study. Recommended doses from phase I comprised radiotherapy (45 Gy in 25 fractions over 5 weeks) with capecitabine 825 mg/m² twice daily × 33 plus sorafenib 400 mg/d. Median daily dose intensity in phase II was radiotherapy 100%, capecitabine 98.6%, and sorafenib 100%. The pCR rate (Dworak 3/4) was 60% (95% CI, 43.3–75.1%) by central independent pathologic review. Sphincter preservation was achieved in 89.5%, R0 resection in 94.7%, and downstaging in 81.6%. The most common grade 3 toxicities during phase II included diarrhoea (15.0%), skin toxicity outside radiotherapy field (12.5%), pain (7.5%), skin toxicity in radiotherapy field, proctitis, fatigue and cardiac ischaemia (each 5%).ConclusionsCombining sorafenib and standard chemoradiotherapy with capecitabine is highly active in patients with KRAS-mutated LARC with acceptable toxicity and deserves further investigation. http://ift.tt/PmpYKN: NCT00869570.

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Metastatic cutaneous apocrine adenocarcinoma responsive to the programmed cell death protein 1 inhibitor pembrolizumab

Publication date: Available online 11 December 2017
Source:European Journal of Cancer
Author(s): Max Rogatsch, Johannes Schmid, Sigurd Lax, Maximilian Uranitsch, Karin Schmid-Zalaudek, Roberta Giuffrida, Iris Zalaudek

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Survival prediction in pancreatic cancer patients with no distant metastasis: a large-scale population-based estimate

Future Oncology, Ahead of Print.

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Atypical chronic myeloid leukemia: a rare entity with management challenges

Future Oncology, Ahead of Print.

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Atypical chronic myeloid leukemia: a rare entity with management challenges

Future Oncology, Ahead of Print.

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Survival prediction in pancreatic cancer patients with no distant metastasis: a large-scale population-based estimate

Future Oncology, Ahead of Print.

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Pathology of retroperitoneal sarcomas: A brief review

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Pathology of retroperitoneal sarcomas: A brief review

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Effectiveness of Online Cancer Education for Nurses and Allied Health Professionals; a Systematic Review Using Kirkpatrick Evaluation Framework

Abstract

Embedding online learning within higher education can provide engaging, cost-effective, interactive and flexible education. By evaluating the impact, outcomes and pedagogical influence of online cancer and education, future curricula can be shaped and delivered by higher education providers to better meet learner, health care provider and educational commissioners' requirements for enhanced patient care and service delivery needs. Using the Kirkpatrick's four-level model of educational evaluation, a systematic review of the effectiveness of online cancer education for nurses and allied health professionals was conducted. From 101 articles, 30 papers were included in the review. Educational theory is not always employed. There is an absence of longitudinal studies to examine impact; an absence of reliability and/or validity testing of measures, limited experimental designs taking account of power and few attempts to mitigate bias. There is, however, an emerging innovative use of mobile/spaced learning techniques. Evidence for clinical and educational effectiveness is weak offering insights into experiences and participant perceptions rather than concrete quantitative data and patient-reported outcomes. More pedagogical research is merited to inform effective evaluation of online cancer education, which incorporates and demonstrates a longer-term impact.

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Effectiveness of Online Cancer Education for Nurses and Allied Health Professionals; a Systematic Review Using Kirkpatrick Evaluation Framework

Abstract

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Effectiveness of Online Cancer Education for Nurses and Allied Health Professionals; a Systematic Review Using Kirkpatrick Evaluation Framework

Abstract

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Effectiveness of Online Cancer Education for Nurses and Allied Health Professionals; a Systematic Review Using Kirkpatrick Evaluation Framework

Abstract

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TNM stage at diagnosis is more predictive of prognosis than pathological complete response in young breast cancer treated with neoadjuvant chemotherapy

No abstract available

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Structural modification of histone deacetylase inhibitors with a phenylglycine scaffold

During the discovery of histone deacetylase inhibitors (HDACIs) as antitumor drugs, a series of potent phenylglycine-based HDACIs were developed. However, further development is restricted by the poor solubility. Therefore, structural modifications were performed in the present study in the development of potent HDACIs with improved pharmacokinetic properties. The synthesized molecules were designed by the substitution of fatty linkers for aromatic linkers, and showed good solubility profiles. Among the compounds derived, molecule HD9 showed a potent enzyme-inhibitory effect (IC50 values of 76 nmol/l) and in-vitro antiproliferative activities (IC50 values of 0.51, 0.83, and 0.76 µmol/l against U937, K562, and HL60 cells, respectively). Molecule HD9 showed selectivity of HDAC3 over HDAC6 in the isoform selectivity assays. Molecular docking studies showed good binding patterns of molecule HD9 to the active site of HDAC3. Results from the present work indicated that molecule HD9 is a promising lead compound for the tumor therapy. Correspondence to Dr Lei Zhang, Department of Medicinal Chemistry, School of Pharmacy, Weifang Medical University, Weifang 261053, China Tel: +86 150 9208 5925; fax: +86 053 6846 2014; e-mail: leiqdu@foxmail.com Correspondence to Dr Weiguo Song, Department of Medicinal Chemistry, School of Pharmacy, Weifang Medical University, Weifang 261053, China Fax: +86 053 6846 2014 Received February 13, 2017 Accepted November 8, 2017 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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TNM stage at diagnosis is more predictive of prognosis than pathological complete response in young breast cancer treated with neoadjuvant chemotherapy

No abstract available

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Ribociclib Extends Survival in HR+ Breast Cancer [News in Brief]

The CDK4/6 inhibitor plus standard therapy demonstrates effectiveness in premenopausal and perimenopausal women.

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Fusobacterium Travels with Colorectal Cancer Cells [News in Brief]

An innate tumor microbiome appears to drive tumor growth.

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Race disparities in the contribution of miRNA isoforms and tRNA-derived fragments to triple-negative breast cancer

Triple-Negative Breast Cancer (TNBC) is a breast cancer subtype characterized by marked differences between White and Black/African-American women. We performed a systems-level analysis on datasets from The Cancer Genome Atlas (TCGA) to elucidate how the expression patterns of messenger RNAs (mRNAs) are shaped by regulatory non-coding RNAs (ncRNAs). Specifically, we studied isomiRs, i.e. isoforms of microRNAs (miRNAs), and tRNA-derived fragments (tRFs). In normal breast tissue, we observed a marked cohesiveness in both the ncRNA and mRNA layers and the associations between them. This cohesiveness was widely disrupted in TNBC: many mRNAs become either differentially expressed or differentially wired between normal breast and TNBC in tandem with isomiR or tRF dysregulation. The affected pathways included energy metabolism, cell signaling and immune responses. Within TNBC, the wiring of the affected pathways with isomiRs and tRFs differed in each race. Multiple isomiRs and tRFs arising from specific miRNA loci (e.g., miR-200c, miR-21, the miR-17/92 cluster, the miR-183/96/182 cluster) and from specific tRNA loci (e.g. the nuclear tRNAGly and tRNALeu, the mitochondrial tRNAVal and tRNAPro) were strongly associated with the observed race disparities in TNBC. We highlight the race-specific aspects of transcriptome wiring by discussing in detail the metastasis-related MAPK and the Wnt/β-catenin signaling pathways, two of the many key pathways that were found differentially wired. In conclusion, by employing a data- and knowledge-driven approach we comprehensively analyzed the normal and cancer transcriptomes to uncover novel key contributors to the race-based disparities of TNBC.

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Coactivation of estrogen receptor and IKK-{beta} induces a dormant metastatic phenotype in ER-positive breast cancer

A growing body of evidence suggests that the inflammatory NFκB pathway is associated with the progression of ER+ tumors to more aggressive stages. However, it is unknown whether NFκB is a driver or a consequence of aggressive ER+ disease. To investigate this question, we developed breast cancer cell lines expressing an inducible, constitutively active form of IκB kinase β (CA-IKKβ), a key kinase in the canonical NFκB pathway. We found that CA-IKKβ blocked E2-dependent cell proliferation in vitro and tumor growth in vivo in a reversible manner, suggesting that IKKβ may contribute to tumor dormancy and recurrence of ER+ disease. Moreover, coactivation of ER and IKKβ promoted cell migration and invasion in vitro and drove experimental metastasis in vivo. Gene expression profiling revealed a strong association between ER and CA-IKKβ-driven gene expression and clinically relevant invasion and metastasis gene signatures. Mechanistically, the invasive phenotype appeared to be driven by an expansion of a basal/stem-like cell population rather than EMT. Taken together, our findings suggest that coactivation of ER and the canonical NFκB pathway promotes a dormant, metastatic phenotype in ER+ breast cancer and implicates IKKβ as a driver of certain features of aggressive ER+ breast cancer.

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miR-204-5p and miR-211-5p contribute to BRAF inhibitor resistance in melanoma

Melanoma treatment with the BRAF V600E inhibitor vemurafenib (VMF) provides therapeutic benefits but the common emergence of drug resistance remains a challenge. We generated A375 melanoma cells resistant to VMF with the goal of investigating changes in miRNA expression patterns that might contribute to resistance. Increased expression of miR-204-5p and miR-211-5p occurring in VMF-resistant cells was determined to impact VMF response. Their expression was rapidly affected by VMF treatment through RNA stabilization. Similar effects were elicited by MEK and ERK inhibitors but not AKT or Rac inhibitors. Ectopic expression of both miRNA in drug-naive human melanoma cells was sufficient to confer VMF resistance and more robust tumor growth in vivo. Conversely, silencing their expression in resistant cells inhibited cell growth. Joint overexpression of miR-204-5p and miR-211-5p durably stimulated Ras and MAPK upregulation after VMF exposure. Overall, our findings show how upregulation of miR-204-5p and miR-211-5p following VMF treatment enables the emergence of resistance, with potential implications for mechanism-based strategies to improve VMF responses.

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LNMICC promotes nodal metastasis of cervical cancer by reprogramming fatty acid metabolism

Cancer spread to lymph nodes (LN) predicts poor survival but underlying mechanisms remain little understood. In this study, we show that overexpression of the long non-coding RNA LNMICC associates with LN metastasis of primary cervical cancer, where it serves as an independent high-risk factor in patient survival. Functional investigations demonstrated that LNMICC promoted LN metastasis by reprogramming fatty acid metabolism, by recruiting the nuclear factor NPM1 to the promoter of the fatty acid binding protein FABP5. We also found that the pro-metastatic effects of LNMICC were directly targeted and suppressed by miR-190. Our results establish a new mechanism of LN metastasis and highlight LNMICC as a candidate prognostic biomarker and therapeutic target in cervical cancer.

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A2AR adenosine signaling suppresses natural killer cell maturation in the tumor microenvironment.

Extracellular adenosine is a key immunosuppressive metabolite that restricts activation of cytotoxic lymphocytes and impairs anti-tumor immune responses. Here, we show that engagement of A2A adenosine receptor (A2AR) acts as a checkpoint that limits the maturation of natural killer (NK) cells. Both global and NK cell-specific conditional deletion of A2AR enhanced proportions of terminally mature NK cells at homeostasis, following reconstitution, and in the tumor microenvironment. Notably, A2AR-deficient, terminally mature NK cells retained proliferative capacity and exhibited heightened reconstitution in competitive transfer assays. Moreover, targeting A2AR specifically on NK cells also improved tumor control and delayed tumor initiation. Taken together, our results establish A2AR-mediated adenosine signaling as an intrinsic negative regulator of NK cell maturation and anti-tumor immune responses. On the basis of these findings, we propose that administering A2AR antagonists concurrently with NK cell-based therapies may heighten therapeutic benefits by augmenting NK cell-mediated anti-tumor immunity.

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Downregulating Neuropilin-2 triggers a novel mechanism enabling EGFR-dependent resistance to oncogene-targeted therapies

Neuropilins are a class of cell surface proteins implicated in cell migration and angiogenesis, with aberrant expression in human tumors. Here we show that the expression of Neuropilin-2 (NRP2) controls EGFR protein levels, thereby impinging on intracellular signaling, viability and response to targeted therapies of oncogene-addicted cells. Notably, increased NRP2 expression in EGFR-addicted tumor cells led to downregulation of EGFR protein and tumor cell growth inhibition. Nrp2 also blunted upregulation of an EGFR "rescue" pathway induced by targeted therapy in Met-addicted carcinoma cells. Cancer cells acquiring resistance to MET oncogene-targeted drugs invariably underwent NRP2 loss, a step required for EGFR upregulation. Mechanistic investigations revealed that NRP2 loss activated NFkB and upregulated the EGFR-associated protein KIAA1199/CEMIP, which is known to oppose the degradation of activated EGFR kinase. Notably, KIAA1199 silencing in oncogene-addicted tumor cells improved therapeutic responses and counteracted acquired drug resistance. Our findings define NRP2 as the pivotal switch of a novel broad-acting and actionable pathway controlling EGFR signaling, and driving resistance to therapies targeting oncogene-addiction.

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CDKN2A/p16 deletion in head and neck cancer cells is associated with Cdk2 activation, replication stress, and vulnerability to Chk1 inhibition

Checkpoint kinase inhibitors (CHKi) exhibit striking single agent activity in certain tumors, but the mechanisms accounting for hypersensitivity are poorly understood. We screened a panel of 49 established human head and neck squamous cell carcinoma (HNSCC) cell lines and report that nearly 20% are hypersensitive to CHKi monotherapy. Hypersensitive cells underwent early S-phase arrest at drug doses sufficient to inhibit greater than 90% of Chk1 activity. Reduced rate of DNA replication fork progression and chromosomal shattering were also observed, suggesting replication stress as a root causative factor in CHKi hypersensitivity. To explore genomic underpinnings of CHKi hypersensitivity, comparative genomic analysis was performed between hypersensitive cells and cells categorized as least sensitive because they showed drug IC50 value greater than the cell panel median and lacked early S phase arrest. Novel association between CDKN2A/p16 copy number loss, Cdk2 activation, replication stress and hypersensitivity of HNSCC cells to CHKi monotherapy was found. Restoring p16 in cell lines harboring CDKN2A/p16 genomic deletions alleviated Cdk2 activation and replication stress, attenuating CHKi hypersensitivity. Taken together, our results suggest a biomarker-driven strategy for selecting HNSCC patients who may benefit the most from CHKi therapy.

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Nkx2-2as suppression contributes to the pathogenesis of Sonic Hedgehog medulloblastoma

Aberrant Hedgehog signaling and excessive activation of the Gli family of transcriptional activators are key drivers of medulloblastoma (MB), the most common human pediatric brain malignancy. MB originates mainly from cerebellar granule neuron progenitors (CGNP), but the mechanisms underlying CGNP transformation remain largely obscure. In this study, we found that suppression of the non-coding RNA Nkx2-2as promotes Sonic Hedgehog (Shh)-potentiated MB development. Nkx2-2as functioned as a competing endogenous RNA (ceRNA) against miR-103 and miR-107, sequestering them and thereby de-repressing their tumor suppressive targets BTG2 and LATS1 and impeding cell division and migration. We also found that Nkx2-2as tethered miR-548m and abrogated its LATS2 targeting activity, Shh signaling impaired Nkx2-2as expression by upregulating the transcriptional repressor FoxD1. In clinical specimens of Shh-subgroup MB we validated coordinated expression of the aforementioned proteins. Notably, exogenous expression of Nkx2-2as suppressed tumorigenesis and prolonged animal survival in MB mouse models. Our findings illuminate the role of non-coding RNAs in Hedgehog signaling and MB occurrence, with implications for identifying candidate therapeutic targets for MB treatment.

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Statin-induced cancer cell death can be mechanistically uncoupled from prenylation of RAS family proteins

The statin family of drugs preferentially trigger tumor cell apoptosis by depleting mevalonate pathway metabolites farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), which are used for protein prenylation, including the oncoproteins of the RAS superfamily. However, accumulating data indicate that activation of the RAS superfamily are poor biomarkers of statin sensitivity, and the mechanism of statin-induced tumor-specific apoptosis remains unclear. Here we demonstrate that cancer cell death triggered by statins can be uncoupled from prenylation of the RAS superfamily of oncoproteins. Ectopic expression of different members of the RAS superfamily did not uniformly sensitize cells to fluvastatin, indicating that increased cellular demand for GGPP and FPP cannot explain increased statin sensitivity. While ectopic expression of HRAS increased statin sensitivity, expression of myristoylated HRAS did not rescue this effect. HRAS-induced epithelial-to-mesenchymal transition (EMT) through activation of zinc finger E-box binding homeobox 1 (ZEB1) sensitized tumor cells to the anti-proliferative activity of statins, and induction of EMT by ZEB1 was sufficient to phenocopy the increase in fluvastatin sensitivity; knocking out ZEB1 reversed this effect. Publicly available gene expression and statin sensitivity databases indicated that enrichment of EMT features was associated with increased sensitivity to statins in a large panel of cancer cell lines across multiple cancer types. These results indicate that the anti-cancer effect of statins is independent from prenylation of RAS family proteins and is associated with a cancer cell EMT phenotype.

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Coactivation of estrogen receptor and IKK-{beta} induces a dormant metastatic phenotype in ER-positive breast cancer

miR-204-5p and miR-211-5p contribute to BRAF inhibitor resistance in melanoma

Transcription factor activities enhance markers of drug sensitivity in cancer

Transcriptional dysregulation induced by aberrant Transcription factors (TFs) is a key feature of cancer, but its global influence on drug sensitivity has not been examined. Here we infer the transcriptional activity of 127 TFs through analysis of RNA-seq gene expression data newly generated for 448 cancer cell lines, combined with publicly available datasets to survey a total of 1,056 cancer cell lines and 9,250 primary tumors. Predicted TF activities are supported by their agreement with independent shRNA essentiality profiles and homozygous gene deletions, and recapitulate mutant-specific mechanisms of transcriptional dysregulation in cancer. By analysing cell line responses to 265 compounds, we uncovered numerous TFs whose activity interacts with anti-cancer drugs. Importantly, combining existing pharmacogenomic markers with TF activities often improves the stratification of cell lines in response to drug treatment. Our results, which can be queried freely at dorothea.opentargets.io, offer a broad foundation for discovering opportunities to refine personalised cancer therapies.

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VEGFR-2-mediated reprogramming of mitochondrial metabolism regulates the sensitivity of acute myeloid leukemia to chemotherapy

Metabolic reprogramming is central to tumorigenesis, but whether chemotherapy induces metabolic features promoting recurrence remains unknown. We established a mouse xenograft model of human acute myeloid leukemia (AML) that enabled chemotherapy-induced regressions of established disease followed by lethal regrowth of more aggressive tumor cells. Human AML cells from terminally ill mice treated with chemotherapy (chemoAML) had higher lipid content, increased lactate production and ATP levels, reduced expression of PPARG coactivator 1α (PGC-1α), and fewer mitochondria than controls from untreated AML animals. These changes were linked to increased vascular endothelial growth factor receptor 2 (VEGFR-2) signaling that counteracted chemotherapy-driven cell death; blocking of VEGFR-2 sensitized chemoAML to chemotherapy (re-)treatment and induced a mitochondrial biogenesis program with increased mitochondrial mass and oxidative stress. Accordingly, depletion of PGC-1α in chemoAML cells abolished such induction of mitochondrial metabolism and chemosensitization in response to VEGFR-2 inhibition. Collectively, this reveals a mitochondrial metabolic vulnerability with potential therapeutic applications against chemotherapy-resistant AML.

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Genomic and Epigenomic Signatures in Ovarian Cancer Associated with Re-sensitization to Platinum Drugs

DNA methylation aberrations have been implicated in acquired resistance to platinum drugs in ovarian cancer (OC). In this study, we elucidated an epigenetic signature associated with platinum drug re-sensitization that may offer utility in predicting the outcomes of patients who are co-administered a DNA methyltransferase inhibitror. The OC specimens we analyzed were derived from a recent clinical trial that compared the responses of patients with recurrent platinum-resistant OC who received carboplatin plus the DNA methyltransferase inhibitor guadecitabine or a standard of care chemotherapy regimen selected by the treating physician. Tumor biopsies or malignant ascites were collected from patients before treatment (day 1, cycle 1) or after treatment (after 2 cycles) for epigenomic and transcriptomic profiling using the Infinium HumanMethylation450 BeadChip (HM450). We defined 94 gene promoters that were hypomethylated significantly by guadecitabine, with 1659 genes differentially expressed in pre-treatment vs. post-treatment tumors. Pathway analysis revealed that the experimental regimen significantly altered immune re-activation and DNA repair pathways. Progression-free survival correlated with baseline expression levels of 1155 genes involved in 25 networks. In functional investigations in OC cells, engineered upregulation of certain signature genes silenced by promoter methylation (DOK2, miR-293a and others) restored platinum drug sensitivity. Overall, our findings illuminate how inhibiting DNA methylation can sensitize OC cells to platinum drugs, in large part by altering gene expression patterns related to DNA repair and immune activation, with implications for improving the personalized care and survival outcomes of OC patients.

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LNMICC promotes nodal metastasis of cervical cancer by reprogramming fatty acid metabolism

A2AR adenosine signaling suppresses natural killer cell maturation in the tumor microenvironment.

Downregulating Neuropilin-2 triggers a novel mechanism enabling EGFR-dependent resistance to oncogene-targeted therapies

CDKN2A/p16 deletion in head and neck cancer cells is associated with Cdk2 activation, replication stress, and vulnerability to Chk1 inhibition

Activation of the Aryl Hydrocarbon Receptor Leads to Resistance to EGFR TKIs in Non-Small-Cell Lung Cancer by Activating Src-Mediated Bypass Signaling

Purpose: The aryl hydrocarbon receptor (AhR) has been generally recognized as a ligand-activated transcriptional factor that responds to xenobiotic chemicals. Recent studies have suggested that the expression of AhR varies widely across different cancer types and cancer cell lines, but its significance in cancer treatment has yet to be clarified. Experimental Design: AhR expression in non-small-cell lung cancer (NSCLC) was determined by Western blotting and IHC staining. In vitro and in vivo functional experiments were performed to determine the effect of AhR on sensitivity to targeted therapeutics. A panel of biochemical assays was used to elucidate the underlying mechanisms. Results: A high AhR protein level indicated an unfavorable prognosis for lung adenocarcinoma. Inhibition of AhR signaling sensitized epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC cells that express high level of endogenous AhR protein. Notably, activation of AhR by pharmacological and molecular approaches rendered EGFR mutant cells resistant to TKIs by restoring PI3K/Akt and MEK/Erk signaling through activation of Src. In addition, we found that AhR acts as a protein adaptor to mediate Jak2-Src interaction, which does not require the canonical transcriptional activity of AhR. Conclusions: Our results reveal a transcription-independent function of AhR and indicate that AhR may act as a protein adaptor that recruits kinases bypassing EGFR and drives resistance to TKIs. Accordingly, targeting Src would be a strategy to overcome resistance to EGFR TKIs in AhR-activated NSCLC.

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Activation of the Aryl Hydrocarbon Receptor Leads to Resistance to EGFR TKIs in Non-Small-Cell Lung Cancer by Activating Src-Mediated Bypass Signaling

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Relevant factors for the optimal duration of extended endocrine therapy in early breast cancer

Abstract

Purpose

For postmenopausal patients with hormone receptor-positive early breast cancer, the optimal subgroup and duration of extended endocrine therapy is not clear yet. The aim of this study using the IDEAL patient cohort was to identify a subgroup for which longer (5 years) extended therapy is beneficial over shorter (2.5 years) extended endocrine therapy.

Methods

In the IDEAL trial, 1824 patients who completed 5 years of adjuvant endocrine therapy (either 5 years of tamoxifen (12%), 5 years of an AI (29%), or a sequential strategy of both (59%)) were randomized between either 2.5 or 5 years of extended letrozole. For each prior therapy subgroup, the value of longer therapy was assessed for both node-negative and node-positive patients using Kaplan Meier and Cox regression survival analyses.

Results

In node-positive patients, there was a significant benefit of 5 years (over 2.5 years) of extended therapy (disease-free survival (DFS) HR 0.67, p = 0.03, 95% CI 0.47–0.96). This effect was only observed in patients who were treated initially with a sequential scheme (DFS HR 0.60, p = 0.03, 95% CI 0.38–0.95). In all other subgroups, there was no significant benefit of longer extended therapy. Similar results were found in patients who were randomized for their initial adjuvant therapy in the TEAM trial (DFS HR 0.37, p = 0.07, 95% CI 0.13–1.06), although this additional analysis was underpowered for definite conclusions.

Conclusions

This study suggests that node-positive patients could benefit from longer extended endocrine therapy, although this effect appears isolated to patients treated with sequential endocrine therapy during the first 5 years and needs validation and long-term follow-up.

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Histone deacetylase inhibitor BG45-mediated HO-1 expression induces apoptosis of multiple myeloma cells by the JAK2/STAT3 pathway

Multiple myeloma (MM) is a hematological malignancy that is characterized by the clonal expansion of plasma cells in the bone marrow. Histone deacetylases (HDACs) represent a new type of molecular targeted therapy for different types of cancers and promising targets for myeloma therapy. We showed that HDAC3 mRNA and protein levels of CD138+ mononuclear cells from MM patients were higher than those in healthy donors. Therefore, we investigated the effects of a novel class I HDAC inhibitor BG45 on MM cells in vitro. BG45 downmodulated heme oxygenase 1 (HO-1) when class I HDACs decreased in MM cells. HO-1 is a target for the treatment of MM. Moreover, BG45 induced hyperacetylation of histone H3 and inhibited the growth, especially the apoptosis of MM cell lines. Treatment with BG45 induced apoptosis by downregulating bcl-2 and Bcl-xl, upregulating Bax and other antiapoptotic proteins and activating poly(ADP-ribose)polymerase, and decreasing protein levels of p-JAK2 and p-STAT3. These effects were partly blocked by HO-1. Correspondingly, BG45 led to an accumulation in the G0/G1 phase, accompanied by decreased levels of CDK4 and phospho-retinoblastoma protein, an increased level of p21, and a moderately reduced level of CDK2. Clinical use of single agents was limited because of toxic side effects and drug resistance. However, combining BG45 with lenalidomide exerted synergistic effects. In conclusion, we verified the potent antimyeloma activity of this novel HDAC inhibitor and that the combination of BG45 and lenalidomide is a new method for MM treatment. Thus, BG45 may be applicable to the treatment of MM and other hematological malignancies.

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A case of heavily pretreated metastatic cardiac angiosarcoma treated successfully using eribulin

Eribulin mesylate (eribulin) is a nontaxane microtubule inhibitor approved in Japan for treating soft tissue sarcoma irrespective of histological subtypes. Thus, our department routinely uses eribulin to treat any histological subtype of sarcoma for patients who have experienced disease progression during standard therapy. However, evidence on the efficacy of eribulin in treating sarcomas that are neither liposarcoma nor leiomyosarcoma is limited. Recently, we encountered a case of a heavily pretreated cardiac angiosarcoma that responded well to eribulin treatment. The patient was a 34-year-old Japanese woman with advanced angiosarcoma, who had been pretreated heavily using several lines of chemotherapy. Eribulin was administered as the eighth line of treatment and the dose was adjusted because of grade 4 neutropenia. After three cycles of treatment, contrast-enhanced computed tomography showed a partial tumor response, which was sustained for ~4 months. This case suggests that eribulin may be a potential therapeutic option for angiosarcoma. Further studies are needed to confirm the benefit of eribulin for patients with angiosarcoma and to establish predictive markers for eribulin sensitivity.

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A genome-wide comprehensive analysis of alterations in driver genes in non-small-cell lung cancer

Lung cancer is one of the most common malignancies and the leading cause of cancer-related deaths worldwide. Although many oncogenes and tumor suppressors have been uncovered in the past decades, the pathogenesis and mechanisms of lung tumorigenesis and progression are unclear. The advancement of high-throughput sequencing technique and bioinformatics methods has led to the discovery of some unknown important protein-coding genes or noncoding RNAs in human cancers. In this study, we tried to identify and validate lung cancer driver genes to facilitate the diagnosis and individualized treatment of patients with this disease. To analyze distinct gene profile in lung cancer, the RNA sequencing data from TCGA and microarray data from Gene Expression Omnibus were used. Then, shRNA-pooled screen data and CRISPR-Cas9-based screen data in lung cancer cells were used to validate the functional roles of identified genes. We found that thousands of gene expression patterns are altered in lung cancer, and genomic alterations contribute to the dysregulation of these genes. Furthermore, we identified some potential lung cancer driver genes, such as TBX2, MCM4, SLC2A1, BIRC5, and CDC20, whose expression is significantly upregulated in lung cancer, and the copy number of these genes is amplified in the genome of patients with lung cancer. More importantly, overexpression of these genes is associated with poorer survival of patients with lung cancer, and knockdown or knockout of these genes results in decreased cell proliferation in lung cancer cells. Taken together, the genomewide comprehensive analysis combined with screen data analyses may provide a valuable help for identifying cancer driver genes for diagnosis and prevention of patients with lung cancer.

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Histone deacetylase inhibitor SAHA-induced epithelial–mesenchymal transition by upregulating Slug in lung cancer cells

SAHA, a member of histone deacetylase inhibitors (HDACIs), which emerged as a class of novel antitumor drug, has been used in clinical treatment of cancers. However, clinical experience of SAHA in solid tumors has been disappointing. Nevertheless, the underlying mechanism of this deficiency is not clearly understood. In the present study, we found that SAHA could induce epithelial–mesenchymal transitions (EMT) in lung cancer A549 cells, which was associated with increased migration capability and cellular morphology changes. We showed that SAHA decreased epithelial marker E-cadherin's expression and increased the expression of mesenchymal marker vimentin. SAHA upregulated the protein and mRNA expression of transcription factor Slug in a time-dependent manner and promoted its nuclear translocation. We further demonstrated that SAHA upregulated Slug expression by promoting Slug acetylation but not influencing the phosphorylation of GSK-3β, a main kinase-controlled Slug expression. Finally, silencing of Slug by siRNA reversed EMT marker expressions and cellular morphology change induced by SAHA, suggesting that Slug plays a crucial role in SAHA-mediated EMT in A549 cells. Our research study provided a better understanding of treatment failure of SAHA in patients with solid tumors. Therefore, more attention should be paid to cancer treatment using SAHA and strategies for reversing EMT before using SAHA would be better if the value of SAHA in the treatment of solid tumors, especially lung cancer, is realized.

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Cell cycle-dependent translocation and regulatory mechanism of CacyBP/SIP in gastric cancer cells

Our previous results showed that calcyclin-binding protein/Siah-1-interacting protein (CacyBP/SIP) inhibits the proliferation and tumorigenicity of gastric cancer; however, the exact mechanism remains unclear, especially from the aspect of cell cycle. The subcellular localization of CacyBP/SIP, Siah-1, and Skp1 in SGC7901 gastric cancer cells was assessed by immunofluorescence after cell cycle synchronization. Levels of CacyBP/SIP, Siah-1, Skp1, β-catenin, and p-ERK1/2 were analyzed by western blotting. CacyBP/SIP phosphorylation (p-CacyBP/SIP) and the combining capacity of Siah-1 and Skp1 with CacyBP/SIP in nucleoprotein were determined by immunoprecipitation. CacyBP/SIP, Siah-1, and Skp1 were mainly in the cytoplasm in the G1 phase, but translocated to the nucleus during G2. Their expression in total protein was not altered, but elevated in the G2 phase in nucleoprotein. The CacyBP/SIP nucleus translocation of cells transfected with mutant CacyBP/SIP that does not bind S100 (CacyBP–ΔS100) was significantly increased compared with wild-type CacyBP/SIP. In the G2 phase, p-CacyBP/SIP expression and the combining capacity of Siah-1 and Skp1 with CacyBP/SIP were all increased, whereas levels of β-catenin and p-ERK1/2 reduced, compared with the G1 phase. CacyBP/SIP or CacyBP–ΔS100 overexpression was correlated with constitutively low β-catenin expression and affected its level through cell cycle. CacyBP/SIP overexpression led to retarded proliferation, G1 arrest, and β-catenin reduction, which could be abolished by lithium chloride, β-catenin activator, and further enhanced by the Wnt inhibitor XAV-939. In addition, CacyBP–ΔS100 further suppressed cell proliferation and induced G1 arrest compared with CacyBP/SIP. In conclusion, CacyBP/SIP nuclear localization, dependent on S100 protein, suppresses gastric cancer tumorigenesis through β-catenin degradation and the dephosphorylation of ERK1/2 during the G2 phase.

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Autophagy and doxorubicin resistance in cancer

Doxorubicin (DOX), also known as adriamycin, is a DNA topoisomerase II inhibitor and belongs to the family of anthracycline anticancer drugs. DOX is used for the treatment of a wide variety of cancer types. However, resistance among cancer cells has emerged as a major barrier to effective treatment using DOX. Currently, the role of autophagy in cancer resistance to DOX and the mechanisms involved have become one of the areas of intense investigation. More and more preclinical data are being obtained on reversing DOX resistance through modulation of autophagy as one of the promising therapeutic strategies. This review summarizes the recent advances in autophagy-targeting therapies that overcome DOX resistance from in-vitro studies to animal models for exploration of novel delivery systems. In-depth understanding of the mechanisms of autophagy regulation in relation to DOX resistance and development of molecularly targeted autophagy-modulating agents will provide a promising therapeutic strategy for overcoming DOX resistance in cancer treatment.

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Reversine induces autophagic cell death through the AMP-activated protein kinase pathway in urothelial carcinoma cells

Urothelial carcinoma is one of the most common malignancies of the urinary tract. Effective treatment of advanced urothelial carcinoma remains a clinical challenge with poor outcomes in these patients. Previous reports have shown that the expression of aurora kinase is associated with clinical stage and prognosis; hence, aurora kinases are potential targets in urothelial carcinoma therapy. Reversine, an aurora kinase inhibitor, was analyzed for its cytotoxicity in this study. Cell proliferation, flow cytometry, western blotting, and immunofluorescent assay were used to determine the effect of reversine on urothelial carcinoma cells. The results showed that reversine significantly inhibits the growth of urothelial carcinoma cell lines. Reversine induced cell cycle arrest at the G2/M phase, leading to autophagic cell death by activating the AMP-activated protein kinase pathway. Reversine induced significant cell death in urothelial carcinoma cells. Our results suggest that reversine may be a suitably small molecule for treating urothelial carcinoma in the future.

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Influence of the alkylating function of aldo-Ifosfamide on the anti-tumor activity

The present work investigates the influence of different DNA damages caused by different isophosphoramide mustards on the 3-hydroxypropanal-assisted apoptotic antitumor activity of oxazaphosphorine cytostatics using I-aldophosphamide-perhydrothiazine (IAP) and mesyl-I-aldophosphamide-perhydrothiazine (SUM-IAP) for in-vitro and in-vivo experiments. IAP and SUM-IAP hydrolyze spontaneously to the corresponding I-aldophosphamide derivatives. They differ in the chemical structure of the alkylating moiety, whereas IAP has two chlorethyl groups in the SUM-IAP molecule, one chlorethyl group is substituted by a mesylethyl group. With both substances, cytotoxicity studies on P388 tumor cells in vitro and therapy experiments in mice bearing advanced growing P388 tumors were carried out. IAP was significantly more cytotoxic in-vitro than SUM-IAP, but the antitumor activity of SUM-IAP was by order of magnitude higher than the antitumor activity of IAP. The reason for these findings is discussed with respect to the enzymatic cleavage of the various I-aldophosphamide derivatives to the corresponding isophosphoramide mustards and 3-hydroxypropanal. Overall, the findings indicate that antitumor activity of ifosfamide and derivatives of ifosfamide can be improved considerably by altering the alkylating moiety of the molecule, but retaining the aldophosphamide structure.

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A SRSF1 self-binding mechanism restrains Mir505-3p from inhibiting proliferation of neural tumor cell lines

Srsf1 has currently been demonstrated to be an oncogene that is precisely autoregulated for normal physiology. Although Mir505-3p has been reported as one of the regulatory miRNAs of Srsf1 in mouse embryonic fibroblast (MEF), the inhibitory effect of Mir505-3p on Srsf1 is poorly described in neural tumors. Whether SRSF1 autoregulation interferes with miRNA targeting on the Srsf1 transcript is unclear. In this work, we screened out one target site, out of three potential target sites on 3′ UTR of Srsf1 transcript, that was required for Mir505-3p targeting. We showed that Mir505-3p was capable of inhibiting tumor proliferation driven by SRSF1 in two neural tumor cell lines, Neuro-2a (N2a) and U251, exclusively in serum-reduced condition. We observed that the protein level of SRSF1 was gradually promoted by increasing concentration of serum. We also found that overexpressed exogenous SRSF1 protein abolished this RNA interfering related targeting, suggesting that serum-rich condition restrains Mir505-3p from inhibiting Srsf1 transcript after inducing SRSF1 protein overexpression. Moreover, by applying bioinformatic analysis, the SRSF1 self-binding motif was found proximal to the Mir505-3p target site, which was required for a SRSF1 competitive self-binding interaction. The interaction of overexpressed exogenous SRSF1 protein and the SRSF1 self-binding motif was sufficient to restrain Mir505-3p from targeting the Srsf1 transcript. These results provide a better understanding of how tumorous microenvironment influences anticancer therapy in the neural system, suggesting potential strategic design for anticancer drugs.

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Anticancer effect of acid ceramidase inhibitor ceranib-2 in human breast cancer cell lines MCF-7, MDA MB-231 by the activation of SAPK/JNK, p38 MAPK apoptotic pathways, inhibition of the Akt pathway, downregulation of ERα

Acid ceramidase is the key enzyme of the ceramide metabolic pathway, which plays a vital role in regulating ceramide – sphingosine-1-phosphate rheostat. Ceramide acts as a proapoptotic molecule, but its metabolite sphingosine-1-phosphate, in contrast, signals for cell proliferation, cell survival, and angiogenesis. Acid ceramidase is highly upregulated in breast tumors and treatment with an acid ceramidase inhibitor, ceranib-2, significantly induced apoptosis in human breast cancer cell lines. However, the mechanisms underlying the induction of apoptosis remain ambiguous to date. Hence, in the present study, we have explored ceranib-2-mediated apoptotic signaling pathways in human breast cancer cell lines. MCF-7 and MDA MB-231 cells were treated with IC50 doses of ceranib-2 and tamoxifen. Nuclear changes showed the apoptotic effect of ceranib-2 in both the cell lines. Loss in the mitochondrial membrane potential was observed only in ceranib-2-treated MCF-7 cells. Ceranib-2 activated intrinsic and extrinsic apoptotic pathways in MCF-7 cells, but only the extrinsic apoptotic pathway was activated in MDA MB-231 cells. Further, ceranib-2 induced apoptosis by activating SAPK/JNK (stress-activated protein kinase/c-Jun N-terminal kinase), p38 MAPK (mitogen-activated protein kinase) apoptotic pathways and by inhibiting the Akt (antiapoptotic) pathway in both the cell lines. Most importantly, ERα (estrogen receptor-α) expression was highly downregulated after ceranib-2 treatment and a docking study predicted the highest binding affinity of ceranib-2 than tamoxifen with ERα in MCF-7 cells. Hence, ceranib-2 may have potential as a chemotherapeutic drug of breast cancer.

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Temozolomide treatment of a malignant pheochromocytoma and an unresectable MAX-related paraganglioma

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors with a strong genetic background. The mainstay of treatment for PCC/PGLs is surgery. However, for unresectable lesions, no curative treatment is currently available. Temozolomide (TMZ) has been shown to determine radiological and biochemical response in malignant PCC/PGLs. We report two cases of PCC/PGLs treated with TMZ. Case 1 is a 51-year-old man with local and distant recurrence (liver and bone metastases) of right adrenal PCC. Case 2 is a 54-year-old woman with a PCC/PGL syndrome caused by a mutation in MAX gene (c.171+1G>A), operated on for bilateral adrenal PCC and presenting with a large unresectable abdominal PGL. Both patients presented hypertension due to catecholamine hypersecretion. TMZ determined radiological response according to RECIST criteria, reduction of urinary catecholamine levels, and controlled hypertension in both patients. Furthermore, the current study demonstrates, for the first time, that MAX-related PGLs are responsive to TMZ.

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Histone deacetylase inhibitor BG45-mediated HO-1 expression induces apoptosis of multiple myeloma cells by the JAK2/STAT3 pathway

A case of heavily pretreated metastatic cardiac angiosarcoma treated successfully using eribulin

A genome-wide comprehensive analysis of alterations in driver genes in non-small-cell lung cancer

Histone deacetylase inhibitor SAHA-induced epithelial–mesenchymal transition by upregulating Slug in lung cancer cells

Cell cycle-dependent translocation and regulatory mechanism of CacyBP/SIP in gastric cancer cells

Autophagy and doxorubicin resistance in cancer

Reversine induces autophagic cell death through the AMP-activated protein kinase pathway in urothelial carcinoma cells

Influence of the alkylating function of aldo-Ifosfamide on the anti-tumor activity

A SRSF1 self-binding mechanism restrains Mir505-3p from inhibiting proliferation of neural tumor cell lines

Integrated safety summary for trifluridine/tipiracil (TAS-102)

Trifluridine/tipiracil, an oral treatment combining trifluridine (an antineoplastic thymidine-based nucleoside analog) and tipiracil hydrochloride (a thymidine phosphorylase inhibitor), led to significant improvement in overall survival in metastatic colorectal cancer (mCRC) patients refractory to standard therapy in the phase III RECOURSE trial. Here, we report an integrated summary of the safety of trifluridine/tipiracil. The main safety analysis includes integrated data from the RECOURSE and J003 studies (safety data group 2) of patients with refractory mCRC receiving trifluridine/tipiracil at the recommended starting dose: 35 mg/m2 twice daily for 5 days with 2 days' rest for 2 weeks, followed by a 14-day rest (one cycle). Integrated data from a larger group of mCRC patients receiving trifluridine/tipiracil at the recommended starting dose (group 1) and nonintegrated data on serious adverse events (SAEs) representing all clinical experience with trifluridine/tipiracil as of the data cutoff date (group 3) are also summarized. In group 2, myelosuppressive and all-grade gastrointestinal adverse events (AEs) were more frequent in trifluridine/tipiracil patients than in placebo patients. The trifluridine/tipiracil and placebo patients had similar frequencies of AEs leading to discontinuation (9.0 vs. 11.5%) and SAEs (27.7 vs. 29.2%); fatal AEs were more frequent in placebo patients than in trifluridine/tipiracil patients (9.3 vs. 2.8%). AEs leading to interruptions/delays/reductions were more frequent in trifluridine/tipiracil patients (56.3 vs. 12.7%). Trifluridine/tipiracil was generally well tolerated, but over 50% of patients required interruptions/delays/reductions. There was a low rate of discontinuations, SAEs, and fatal AEs. This analysis confirms the safety profile observed in RECOURSE.

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Anticancer effect of acid ceramidase inhibitor ceranib-2 in human breast cancer cell lines MCF-7, MDA MB-231 by the activation of SAPK/JNK, p38 MAPK apoptotic pathways, inhibition of the Akt pathway, downregulation of ERα

Temozolomide treatment of a malignant pheochromocytoma and an unresectable MAX-related paraganglioma

The Role of B-Cell Maturation Antigen in the Biology and Management of, and as a Potential Therapeutic Target in, Multiple Myeloma

Abstract

B-cell maturation antigen (BCMA) was originally identified as a cell membrane receptor, expressed exclusively on late stage B-cells and plasma cells (PCs). Investigations of BCMA as a target for therapeutic intervention in multiple myeloma (MM) were initiated in 2007, using cSG1 as a naked antibody (Ab) as well as an Ab–drug conjugate (ADC) targeting BCMA, ultimately leading to ongoing clinical studies for previously treated MM patients. Since then, multiple companies have developed anti-BCMA-directed ADCs. Additionally, there are now three bispecific antibodies in development, which bind to both BCMA and CD3ε on T-cells. This latter binding results in T-cell recruitment and activation, causing target cell lysis. More recently, T-cells have been genetically engineered to recognize BCMA-expressing cells and, in 2013, the first report of anti-BCMA-chimeric antigen receptor T-cells showed that these killed MM cell lines and human MM xenografts in mice. BCMA is also solubilized in the blood (soluble BCMA [sBCMA]) and MM patients with progressive disease have significantly higher sBCMA levels than those responding to treatment. sBCMA circulating in the blood may limit the efficacy of these anti-BCMA-directed therapies. When sBCMA binds to B-cell activating factor (BAFF), BAFF is unable to perform its major biological function of inducing B-cell proliferation and differentiation into Ab-secreting PC. However, the use of γ-secretase inhibitors, which prevent shedding of BCMA from PCs, may improve the efficacy of these BCMA-directed therapies.

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Lipoxin A4 reverses mesenchymal phenotypes to attenuate invasion and metastasis via the inhibition of autocrine TGF-β1 signaling in pancreatic cancer

Pancreatic cancer is a lethal disease in part because of its potential for aggressive invasion and metastasis. Lipoxin A4 (LXA4) is one of the metabolites that is derived from arachidonic acid and that is cata...

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Primary Esophagogastric Neuroendocrine Carcinoma: a Retrospective Study from the Nottingham Upper Gastrointestinal Cancer Center

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Primary Esophagogastric Neuroendocrine Carcinoma: a Retrospective Study from the Nottingham Upper Gastrointestinal Cancer Center

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Survival and prognostic factors of non-small cell lung cancer patients with postoperative locoregional recurrence treated with radical radiotherapy

Locoregional recurrence remains the challenge for long-term survival of non-small cell lung cancer (NSCLC) patients after radical surgery, and curative-intent radiotherapy could be a treatment choice. This stu...

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Survival and prognostic factors of non-small cell lung cancer patients with postoperative locoregional recurrence treated with radical radiotherapy

Postoperative thrombocytopenia: why you should consider antiplatelet therapy?

Purpose of review This review addresses the role of platelets in perioperative ischemic complications involving the brain, kidneys, and gastrointestinal tract, and long-term survival in patients undergoing coronary artery bypass grafting surgery. Importantly, findings of several recent clinical studies will be discussed with emphasis on platelet activation and leukocyte inflammatory responses as important mediators of vascular microthrombosis and ischemic injury. Recent findings Our recent findings suggest that in some patients, the hemostatic balance during and after surgery may shift toward a hypercoagulable state and contribute to acute organ failure. Summary For over 6 decades, major postoperative complications after cardiac surgery have remained unchanged. The potential influence of microthrombosis involving platelets has been underappreciated and use of perioperative antiplatelet therapy remains very limited – primarily because of a culture of fear of bleeding. Correspondence to Manuel L. Fontes, MD, Professor of Anesthesiology and Critical Care, Yale University School of Medicine, 333 Cedar Street, TMP-3, P.O. Box 208051, New Haven, CT 06520, USA. Tel: +1 203 785 2802; e-mail: manuel.fontes@yale.edu Copyright © 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Perioperative steroid therapy: where's the evidence?

Purpose of review Review of historical and current evidence of adrenal suppression in patients on chronic glucocorticoid therapy during perioperative period, and discussion of current recommendations for perioperative stress dose steroid administration. Recent findings Evidence suggests low incidence of perioperative adrenal insufficiency in patients receiving chronic glucocorticoid therapy. Recent studies show no difference in survival or hemodynamic sequella by withholding perioperative stress steroids; however, these studies are limited in size and universal applicability. Summary Current recommendations for perioperative stress dose steroids for patients on chronic glucocorticoid therapy are based on duration and dose of maintenance steroids. All patients should take their regular daily dose of steroid preoperatively regardless of dose or chronicity of prior treatment. Additional, stress dose steroid dosing is based on patient risk of adrenal suppression and surgical complexity and stress. Correspondence to Leon Freudzon, MD, 333 Cedar Street, TMP 3, P.O. Box 208051, New Haven, CT 06520-8051, USA. Tel: +1 203 785 2802; e-mail: leon.freudzon@yale.edu Copyright © 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Impact of pectoral nerve block on postoperative pain and quality of recovery in patients undergoing breast cancer surgery: A randomised controlled trial

BACKGROUND In recent years, thoracic wall nerve blocks, such as the pectoral nerve (PECS) block and the serratus plane block have become popular for peri-operative pain control in patients undergoing breast cancer surgery. The effect of PECS block on quality of recovery (QoR) after breast cancer surgery has not been evaluated. OBJECTIVES To evaluate the ability of PECS block to decrease postoperative pain and anaesthesia and analgesia requirements and to improve postoperative QoR in patients undergoing breast cancer surgery. DESIGN Randomised controlled study. SETTING A tertiary hospital. PATIENTS Sixty women undergoing breast cancer surgery between April 2014 and February 2015. INTERVENTIONS The patients were randomised to receive a PECS block consisting of 30 ml of levobupivacaine 0.25% after induction of anaesthesia (PECS group) or a saline mock block (control group). The patients answered a 40-item QoR questionnaire (QoR-40) before and 1 day after breast cancer surgery. MAIN OUTCOME MEASURES Numeric Rating Scale score for postoperative pain, requirement for intra-operative propofol and remifentanil, and QoR-40 score on postoperative day 1. RESULTS PECS block combined with propofol–remifentanil anaesthesia significantly improved the median [interquartile range] pain score at 6 h postoperatively (PECS group 1 [0 to 2] vs. Control group 1 [0.25 to 2.75]; P = 0.018]. PECS block also reduced propofol mean (± SD) estimated target blood concentration to maintain bispectral index (BIS) between 40 and 50 (PECS group 2.65 (± 0.52) vs. Control group 3.08 (± 0.41) μg ml−1; P

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Quantitative assessment of neuropilin-2 as a simple and sensitive diagnostic assay for spitzoid melanocytic lesions

There is a significant need for the development of diagnostic tools that can precisely distinguish Spitz nevi and spitzoid melanomas. Here, we report the development of a PCR-based quantitative diagnostic assay for spitzoid melanocytic lesions utilizing the expression ratio of neuropilin-2 and melan-A genes in primary tumor specimens. We find that the expression ratio of neuropilin-2/melan-A is significantly increased in spitzoid melanomas compared with Spitz nevi. The diagnostic potential of this quantitative assay was validated in two independent sets of patient samples as demonstrated in a receiver operating characteristic curve analysis showing an area under the curve value of 91.8%. Furthermore, the assay was found to quantitatively distinguish the clinical nature of atypical spitzoid melanocytic lesions that were diagnostically undetermined using histopathologic criteria alone. Our data indicate that this quantitative assay may be used as a tool in determining the diagnostic classification of histologically challenging spitzoid tumors. *Anna Eisenstein and Izabela P. Panova contributed equally to the writing of this article. Correspondence to Byungwoo Ryu, PhD, Department of Dermatology, Boston University School of Medicine, 609 Albany Street, J-502, Boston, MA 02118, USA Tel: +1 617 638 5535; fax: +1 617 638 5515; e-mail: ryub@bu.edu Correspondence to Rhoda M. Alani, MD, Department of Dermatology, Boston University School of Medicine, 609 Albany Street, J-507, Boston, MA 02118, USA Tel: +1 617 638 5517; fax: +1 617 638 5543; e-mail: alani@bu.edu Received August 10, 2017 Accepted October 27, 2017 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Illustrative cases for monitoring by quantitative analysis of BRAF/NRAS ctDNA mutations in liquid biopsies of metastatic melanoma patients who gained clinical benefits from anti-PD1 antibody therapy

Anti-programmed death 1 (PD-1) monoclonal antibodies improve the survival of metastatic melanoma patients. Predictive or monitoring biomarkers for response to this therapy could improve the clinical management of these patients. To date, no established biomarkers are available for monitoring the response to immunotherapy. Tumor- specific mutations in circulating tumor DNA (ctDNA) such as BRAF and NRAS mutations for melanoma patients have been proposed for monitoring of immunotherapy response. We present seven illustrative cases for the use of ctDNA BRAF and NRAS mutations' monitoring in plasma. The cases described exemplify four distinct clinical benefit patterns: rapid and durable complete response (CR), early progression, followed by CR, CR followed by early progression after interrupting treatment and long-term disease stabilization. These representative cases suggest that comprehensive BRAF/NRAS ctDNA monitoring during anti-PD1 therapy is informative and can be of added value for the monitoring of melanoma patients gaining clinical benefit on anti-PD1 treatment. An important advantage of our approach is that using the cartridge system on the Idylla platform for mutation analysis, the results become available the same day 2 h after plasma collection. Therefore, in the future, the ctDNA level can be an element in the clinical management of the patients. *Teofila Seremet and Simon Planken contributed equally to the writing of this article. Correspondence to Teofila Seremet, MD, PhD, Department of Medical Oncology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090 Jette, Brussels, Belgium Tel: +32 24 749 478; fax: +32 24 776 210; e-mail: teofila.caplanusi@uzbrussel.be Received August 10, 2017 Accepted October 30, 2017 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Incidence and predictors of postoperative delirium after cytoreduction surgery-hyperthermic intraperitoneal chemotherapy: Methodological issues

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Reply to comment on: Incidence and predictors of postoperative delirium after cytoreduction surgery-hyperthermic intraperitoneal chemotherapy

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Imaging of liposarcomas for clinicians: Characteristic features and differential considerations

Liposarcoma (LPS) is a malignancy of fat and one of the most common soft tissue sarcomas. There are three major subtypes of LPS: Well-differentiated / dedifferentiated, myxoid, and pleomorphic. We review the imaging features of LPS in the abdomen and extremities, describe features that help differentiate the subtypes, and provides alternative considerations for fat-containing lesions (many benign) that can mimic LPS.

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Concomitant organ resection does not improve outcomes in primary retroperitoneal well-differentiated liposarcoma: A retrospective cohort study at a major sarcoma center

Background

We investigated whether concomitant organ removal as part of the primary resection of RP WDLPS confers an outcome advantage in patients treated at a major sarcoma center.

Methods

The departmental sarcoma database was reviewed to identify patients with RP WDLPS who underwent initial surgical resection for primary disease at MD Anderson Cancer Center during the study period 1995-2011. We retrospectively reviewed medical records and examined associations between clinicopathologic variables and overall survival (OS) as well as disease-free survival (DFS).

Results

Among 83 patients included in this study, 76 patients (92%) underwent complete resection (R0/R1). Concomitant organ resections were performed in 38 patients (46%). Invasion of the resected organ/s was seen in six patients (7%). Estimated OS was 11.3 years (5-year OS, 86%), and DFS was 5.4 years (5-year DFS, 51%). By multivariate analysis, concomitant organ resection was not associated with improved OS (P = 0.428) or DFS (P = 0.946), and lack of organ resection was associated with a lower risk of postoperative complications (P = 0.01).

Conclusions

Concomitant organ resection was not associated with a survival benefit in RP WDLPS in this study. In patients with primary RP WDLPS, we recommend selective resection of contiguous organs only if there is clinical suspicion of invasion.

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Axillary reverse mapping with indocyanine green or isosulfan blue demonstrate similar crossover rates to radiotracer identified sentinel nodes

Background

Sentinel lymph node (SLN) resection is imperative for breast cancer staging. Axillary reverse mapping (ARM) can preserve arm draining nodes and lymphatics during surgery. ARM is generally performed with isosulfan blue (ISB), restricting its use for concurrent SLN biopsy. Indocyanine green (ICG) could serve as an alternative to ISB for ARM procedures.

Methods

SLN mapping and biopsy was performed via periareolar injection of ⁹⁹technetium-sulfur colloid (^99mTcSc, TSC). ISB and ICG were injected in the upper arm. Blue-stained lymphatics or nodes were visualized in the axilla; ICG was identified using the SPY Elite® system.

Results

Twenty-three patients underwent SLN biopsy with or without axillary node dissection and ARM procedures. Twenty of these patients had at least one hot node; 12 patients had SLNs that were only hot, 6 hot/blue/fluorescent, and 2 hot/fluorescent. Overall, crossover of ARM agents with SLNs occurred in 8 cases. Inspection of the axillary cavity after SLN biopsy revealed fluorescent lymphatics and nodes remaining in 14 and 7 patients, respectively. Blue lymphatics and blue nodes were detected in fewer cases.

Conclusion

Nearly one-third of patients showed crossover between breast and arm draining nodes, which provides insight as to why some patients develop lymphedema symptoms after SLN biopsy. ICG and ISB identify similar numbers of SLNs. As such ICG could substitute for ISB in ARM procedures.

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Melanoma patterns of care in Ontario: A call for a strategic alignment of multidisciplinary care

Background and Objectives

Variability in melanoma management has prompted concerns about equitable and timely treatment. We investigated patterns of melanoma diagnosis and treatment using population-level data.

Methods

Patients with invasive cutaneous melanoma were identified retrospectively from the Ontario Cancer Registry (2003-2012) and deterministically linked with administrative databases to identify incidence, disease characteristics, geographic origin, and multimodal treatment within a year of diagnosis. Melanoma treatment was categorized as inadequate or adequate based on multidisciplinary clinical algorithms. Multivariable logistic regression was used to model factors associated with treatment adequacy.

Results

From 2003 to 2012, 22 918 patients with invasive melanoma were identified with annual age/sex standardized incidence rates of 11.7-14.3/100 000 for females and 13.4-15.9/100 000 for males. Melanoma occurred at median age of 62 and primarily on extremities (43.9%). Within 1 year after diagnosis, 86.7% of patients received surgery as primary therapy. A total of 2312 (10.6%) patients received inadequate or no treatment after diagnosis. Receiving adequate treatment was associated with consultation with dermatology (OR 1.92, CI 1.71-2.14), plastic surgery (OR 4.80, CI 4.32-5.34), or general surgery (OR 2.15, CI 1.94-2.38).

Conclusions

Significant variation exists in melanoma management and nearly one in nine patients is inadequately treated. Referral to sub-specialized providers is critical for ensuring appropriate care.

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