Overexpression of SHCBP1 promotes migration and invasion in gliomas by activating the NF‐κB signaling pathway

Molecular Carcinogenesis, EarlyView.


https://ift.tt/2KEKVj7

Bitter melon juice exerts its efficacy against pancreatic cancer via targeting both bulk and cancer stem cells

Molecular Carcinogenesis, EarlyView.


https://ift.tt/2IyFKVy

hTERT promotes tumor progression by enhancing TSPAN13 expression in osteosarcoma cells

Molecular Carcinogenesis, EarlyView.


https://ift.tt/2KEKLZ3

lncRNA DLEU1 contributes to tumorigenesis and development of endometrial carcinoma by targeting mTOR

Molecular Carcinogenesis, EarlyView.


https://ift.tt/2It9rXK

Carcinosarcoma of Breast Mimicking Breast Abscess

Abstract

Carcinosarcoma, a tumor having both carcinomatous and sarcomatous elements, occurring in the breast, is a rare condition. The tumor consists of both epithelial and mesenchymal cell lines and tends to behave aggressively. It has clinical features like that of invasive breast carcinoma but sometimes there can be diagnostic confusion as it can mimic or present as breast abscess. Treatment is multimodal. Surgery plays the vital role. Post-op radiation and chemo are indicated. Hormone therapy is usually inapplicable as most of the time, it is hormone receptor negative.

https://ift.tt/2KBTlHT

Negative prognostic factors and resulting clinical outcome in patients with metastatic renal cell carcinoma included in the Italian nivolumab-expanded access program

Future Oncology, Ahead of Print.


https://ift.tt/2GuWzL9

Cancers, Vol. 10, Pages 149: AZD1775 Increases Sensitivity to Olaparib and Gemcitabine in Cancer Cells with p53 Mutations

Cancers, Vol. 10, Pages 149: AZD1775 Increases Sensitivity to Olaparib and Gemcitabine in Cancer Cells with p53 Mutations

Cancers doi: 10.3390/cancers10050149

Authors: Xiangbing Meng Jianling Bi Yujun Li Shujie Yang Yuping Zhang Mary Li Haitao Liu Yiyang Li Megan E. Mcdonald Kristina W. Thiel Kuo-Kuang Wen Xinhao Wang Meng Wu Kimberly K. Leslie

Tumor suppressor p53 is responsible for enforcing cell cycle checkpoints at G1/S and G2/M in response to DNA damage, thereby allowing both normal and tumor cells to repair DNA before entering S and M. However, tumor cells with absent or mutated p53 are able to activate alternative signaling pathways that maintain the G2/M checkpoint, which becomes uniquely critical for the survival of such tumor cells. We hypothesized that abrogation of the G2 checkpoint might preferentially sensitize p53-defective tumor cells to DNA-damaging agents and spare normal cells with intact p53 function. The tyrosine kinase WEE1 regulates cdc2 activity at the G2/M checkpoint and prevents entry into mitosis in response to DNA damage or stalled DNA replication. AZD1775 is a WEE1 inhibitor that overrides and opens the G2/M checkpoint by preventing WEE1-mediated phosphorylation of cdc2 at tyrosine 15. In this study, we assessed the effect of AZD1775 on endometrial and ovarian cancer cells in the presence of two DNA damaging agents, the PARP1 inhibitor, olaparib, and the chemotherapeutic agent, gemcitabine. We show that AZD1775 alone is effective as a therapeutic agent against some p53 mutated cell models. Moreover, the combination of AZD1775 with olaparib or gemcitabine is synergistic in cells with mutant p53 and constitutes a new approach that should be considered in the treatment of advanced and recurrent gynecologic cancer.

https://ift.tt/2rRBTIq

Combined VEGF and PD-L1 blockade displays synergistic treatment effects in an autochthonous mouse model of small cell lung cancer

Small cell lung cancer (SCLC) represents the most aggressive pulmonary neoplasm and is often diagnosed at late stage with limited survival, despite combined chemotherapies. We show in an autochthonous mouse model of SCLC that combined anti-VEGF/anti-PD-L1 targeted therapy synergistically improves treatment outcome compared to anti-PD-L1 and anti-VEGF monotherapy. Mice treated with anti-PD-L1 alone relapsed after 3 weeks and were associated with a tumor-associated PD-1/TIM-3 double positive exhausted T cell phenotype. This exhausted T cell phenotype upon PD-L1 blockade was abrogated by the addition of anti-VEGF targeted treatment. We confirmed a similar TIM-3 positive T cell phenotype in PBMC of SCLC patients with adaptive resistance to anti-PD-1 treatment. Mechanistically, we show that VEGF-A enhances co-expression of the inhibitory receptor TIM-3 on T cells, indicating an immunosuppressive function of VEGF in SCLC patients during anti-PD-1 targeted treatment. Our data strongly suggest that a combination of anti-VEGF and anti-PD-L1 therapies can be an effective treatment strategy in patients with SCLC.

https://ift.tt/2k9zWmM

SHP-1 acts as a Tumor Suppressor in Hepatocarcinogenesis and HCC Progression

Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1, also known as PTPN6), is a nonreceptor protein tyrosine phosphatase that acts as a negative regulator of inflammation. Emerging evidence indicates that SHP-1 plays a role in inhibiting the progression of hepatocellular carcinoma (HCC). However, the role of SHP-1 in hepatocarcinogenesis remains unknown. Here we find that levels of SHP-1 are significantly downregulated in human HCC tissues compared with those in noncancerous tissues (P < 0.001) and inversely correlate with tumor diameters (r = -0.4130, P = 0.0002) and serum alpha-fetoprotein(AFP) levels (P = 0.047). Reduced SHP-1 expression was associated with shorter overall survival of HCC patients with HBV infection. Overexpression of SHP-1 suppressed proliferation, migration, invasion and tumorigenicity of HCC cells, whereas knockdown of SHP-1 enhanced the malignant phenotype. Moreover, knockout of Ptpn6 in hepatocytes (Ptpn6HKO) enhanced hepatocarcinogenesis induced by diethylnitrosamine (DEN) as well as metastasis of primary liver cancer in mice. Furthermore, systemic delivery of SHP-1 by an adenovirus expression vector exerted a therapeutic effect in an orthotopic model of HCC in NOD/SCID mice and DEN-induced primary liver cancers in Ptpn6HKO mice. In addition, SHP-1 inhibited the activation of JAK/STAT, NF-κB, and AKT signaling pathways, but not the MAPK pathway in primary hepatocytes from DEN-treated mice and human HCC cells. Together, our data implicate SHP-1 as a tumor suppressor of hepatocarcinogenesis and HCC progression and propose it as a novel prognostic biomarker and therapeutic target of HCC.

https://ift.tt/2rZiaGm

Integrin {beta}3 inhibition enhances the antitumor activity of ALK inhibitor in ALK-rearranged NSCLC

Background: Anaplastic lymphoma kinase (ALK)-positive cancers are sensitive to small molecule ALK kinase inhibitors, but most cases experience failure following treatment. Hence, additional drug targets and combination therapeutic treatments are needed. We investigated gene expression that is regulated by the expression of ALK and explored its roles in cancer progression and therapeutic implication. Patients and methods: We screened ALK-rearranged non-small cell lung cancer (NSCLC) cases using immunohistochemistry and fluorescence in situ hybridization, and then conducted multiplex gene expression analysis. We also performed a clinicopathological analysis to validate the findings. Additional cellular experiments, including inhibition and migration assays, and in vivo lung cancer model studies were performed.  Results: Among patients with ALK-rearranged NSCLC, integrin β3 (ITGB3) was one of the overexpressed genes in comparison with that in ALK-negative NSCLC (P = 0.0003). ALK and integrin β3 expression were positively correlated, and we discovered that high integrin β3 mRNA expression was associated with metastasis and more advanced tumor stages (P < 0.005; P < 0.05). Furthermore, we found that inhibition of both ALK and integrin β3 led to increased drug sensitivity in vitro and in vivo (both P < 0.05).  Conclusions:  We discovered a positive correlation between ALK and integrin β3 expression levels in ALK-rearranged NSCLC. Our findings suggest that high integrin β3 expression in ALK-rearranged NSCLC is associated with tumor progression and a worse prognosis. This demonstrates the prognostic value of integrin β3 and provides a rationale for combination treatment with ALK and integrin β3 inhibitors in patients with ALK-rearranged NSCLC.

https://ift.tt/2KEYy1B

High-fat Diet-induced Inflammation Accelerates Prostate Cancer Growth via IL6 Signaling

Objective: High-fat diet (HFD) could induce prostate cancer progression. The aim of this study is to identify mechanisms of HFD-induced prostate cancer progression, focusing on inflammation. Materials and Methods: We administered HFD and celecoxib to autochthonous immunocompetent Pb-Cre+; Pten(fl/fl) model mice for prostate cancer. Tumor growth was evaluated by tumor weight and Ki67 stain, and local immune cells were assessed by flow cytometry at 22 weeks of age. Cytokines which correlated with tumor growth were identified, and the changes of tumor growth and local immune cells after inhibition of the cytokine signals were evaluated in the mice. Immunohistochemical analyses using prostatectomy specimens of obese patients were performed. Results: HFD accelerated tumor growth, and increased the myeloid-derived suppressor cells (MDSCs) fraction and M2/M1 macrophage ratio in the model mice. Celecoxib suppressed tumor growth, and decreased both local MDSCs and M2/M1 macrophage ratio in HFD-fed mice. HFD-induced tumor growth was associated with IL6 secreted by prostatic macrophages, as were phosphorylated signal transducer and activator of transcription 3 (pSTAT3)-positive tumor cells. Anti-IL6 receptor antibody administration suppressed tumor growth, and decreased local MDSCs and pSTAT3-positive cell fractions in HFD-fed mice. The tumor-infiltrating CD11b-positive cell count was significantly higher in prostatectomy specimens of obese than those of non-obese prostate cancer patients. Conclusions: HFD increased MDSCs and accelerated prostate cancer tumor growth via IL6/pSTAT3 signaling in the mice. This mechanism could exist in obese prostate cancer patients. IL6-mediated inflammation could be a therapeutic target for prostate cancer.

https://ift.tt/2LbCxss

Role of Elevated PHIP Copy Number as a Prognostic and Progression Marker for Cutaneous Melanoma

Purpose: Previous studies have indicated an important role for pleckstrin homology domain-interacting protein (PHIP) as a marker and mediator of melanoma metastasis. Here we aimed to confirm the role of PHIP copy number in successive stages of melanoma progression. Experimental Design: PHIP copy number was examined using fluorescence in situ hybridization (FISH) in three independent cohorts by recording the percentage of cells harboring > 3 copies of PHIP. The impact of PHIP copy number on survival was assessed using Cox regression analysis. The enrichment of PHIP was assessed in various molecular melanoma subtypes. PHIP expression was analyzed in The Cancer Genome Atlas (TCGA) melanoma cohort. Results: Elevated PHIP copy number was significantly predictive of reduced distant metastasis-free survival (DMFS) and disease-specific survival (DSS), and increased prevalence of ulceration in primary melanoma (cohort #1). By multivariate analysis, PHIP FISH scores were independently predictive of DMFS and DSS. PHIP copy number was enriched in metastatic melanomas harboring mutant NRAS or expressing PTEN protein (cohort #2). PHIP copy number was significantly elevated in metastatic melanomas when compared with matched primary tumors from the same patient (cohort #3). Several of these associations were replicated using TCGA cohort analysis. Conclusions: These results underscore the important role of PHIP copy number elevation in melanoma progression, and identify molecular subtypes of melanoma in which PHIP is enriched. Finally, as elevated PHIP copy number appears to be selected for during the progression of primary to metastatic melanoma, these results confirm PHIP as a promising therapeutic target for melanoma.

https://ift.tt/2IuFHG1

The landscape of actionable genomic alterations in cell-free circulating tumor DNA from 21,807 advanced cancer patients

Purpose: Cell-free DNA (cfDNA) sequencing provides a non-invasive method for obtaining actionable genomic information to guide personalized cancer treatment, but the presence of multiple alterations in circulation related to treatment and tumor heterogeneity complicate the interpretation of the observed variants. Experimental Design: We describe the somatic mutation landscape of 70 cancer genes from cfDNA deep-sequencing analysis of 21,807 patients with treated, late-stage cancers across >50 cancer types. To facilitate interpretation of the genomic complexity of circulating tumor DNA in advanced, treated cancer patients, we developed methods to identify cfDNA copy-number driver alterations and cfDNA clonality. Results: Patterns and prevalence of cfDNA alterations in major driver genes for non-small cell lung, breast, and colorectal cancer largely recapitulated those from tumor tissue sequencing compendia (TCGA and COSMIC; r=0.90-0.99), with the principle differences in alteration prevalence being due to patient treatment. This highly sensitive cfDNA sequencing assay revealed numerous subclonal tumor-derived alterations, expected as a result of clonal evolution, but leading to an apparent departure from mutual exclusivity in treatment-naïve tumors. Upon applying novel cfDNA clonality and copy-number driver identification methods, robust mutual exclusivity was observed among predicted truncal driver cfDNA alterations (FDR=5x10^-7 for EGFR and ERBB2), in effect distinguishing tumor-initiating alterations from secondary alterations. Treatment-associated resistance, including both novel alterations and parallel evolution, was common in the cfDNA cohort and was enriched in patients with targetable driver alterations (>18.6% patients). Conclusions: Together these retrospective analyses of a large cfDNA sequencing data set reveal subclonal structures and emerging resistance in advanced solid tumors.

https://ift.tt/2LdFkl8

Therapeutic vaccines and immune checkpoints inhibition options for gynecological cancers

Publication date: Available online 18 May 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Chiara Di Tucci, Michele Carlo Schiavi, Pierangelo Faiano, Ottavia D'Oria, Giovanni Prata, Valentina Sciuga, Andrea Giannini, Innocenza Palaia, Ludovico Muzii, Pierluigi Benedetti Panici
Treatments for gynecological cancer include surgery, chemotherapy, and radiation. However, overall survival is not improved, and novel approaches are needed. Immunotherapy has been proven efficacious in various types of cancers and multiple approaches have been recently developed. Since numerous gynecological cancers are associated to human papilloma virus (HPV) infections, therapeutic vaccines, targeting HPV epitopes, have been developed. The advancing understanding of the immune system, regulatory pathways and tumor microenvironment have produced a major interest in immune checkpoint blockade, Indeed, immune checkpoint molecules are important clinical targets in a wide variety of tumors, including gynecological.In this review, we will describe the immunotherapeutic targets and modalities available and review the most recent immunotherapeutic clinical trials in the context of gynecological cancers. The synergic results obtained from the combination of HPV therapeutic vaccines with radiotherapy, chemotherapy, or immune checkpoint inhibitors, may underlie the potential for a novel therapeutic scenario for these tumors.



https://ift.tt/2x3lS7F

5-Lipoxygenase: its involvement in gastrointestinal malignancies

Publication date: Available online 18 May 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Neha Merchant, Lakkakula Venkata Kameswara Subrahmanya Bhaskar, Saimila Momin, Peela Sujatha, Aramati B.M. Reddy, Ganji Purnachandra Nagaraju
Lipoxygenases (LOXs) are dioxygenases that catalyze the peroxidation of linoleic acid (LA) or arachidonic acid (AA), in the presence of molecular oxygen. The existence of inflammatory component in the tumor microenvironment intimately links the LOXs to gastrointestinal (GI) cancer progression. Amongst the six-different human LOX-isoforms, 5-LOX is the most vital enzyme for leukotriene (LT) biosynthesis, which is the main inflammation intermediaries. As recent investigations have shown the association of 5-LOX with tumor metastasis, there has also been significant progress in discovering the function of 5-LOX pathway in GI cancer. Studies on GI cancer cells using the pharmacological drugs targeting 5-LOX pathway have shown antiproliferative and proapoptotic effects. Pharmacogenetic discoveries in other diseases have revealed strong heritable basis for the leukotriene pathway, which helps in exploring the mechanistic source of genetic alteration within the leukotriene pathway and offer insights into GI cancer pathogenesis and future prospects for treatment and prevention. This review recapitulates the current research status of 5-LOX activity in GI malignancies.



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Editorial Board

Publication date: May 2018
Source:Cancer Treatment Reviews, Volume 66





https://ift.tt/2Iv6amF

Inhibition of fibroblast growth factor receptor-signaling sensitizes imatinib-resistant gastrointestinal stromal tumors to low doses of topoisomerase II inhibitors

The acquired resistance of gastrointestinal stromal tumors (GISTs) to the targeted-based therapy remains the driving force to identify the novel approaches that are capable of increasing the sensitivity of GISTs to the current therapeutic regimens. Our present data show that BGJ398, a selective fibroblast growth factor receptor (FGFR) inhibitor, sensitizes imatinib (IM)-resistant GIST cells with receptor tyrosine kinase (RTK) switch (loss of c-KIT/gain of pFGFR2a) to the low doses of topoisomerase II inhibitors – doxorubicin (Dox) and etoposide (Eto). Mechanistically, pretreatment of IM-resistant GIST cells with BGJ398 for 12 h markedly enhanced proapoptotic and growth-suppressive effects of Dox (or Eto). Indeed, a significant cleavage of PARP and caspase-3 was observed in GIST cells treated with a combination of FGFR and topoisomerase II inhibitor. In contrast, no signs of apoptosis were detected in IM-resistant GIST cells treated with BGJ398, whereas the low doses of Dox (Eto) exerted the minor proapoptotic effects on GISTs. The mechanism of BGJ398-induced sensitization of GIST to topoisomerase II inhibitors might be because of attenuation of DNA damage signaling and repair. Indeed, we observed a marked decrease in Rad51 expression in GIST cells treated with BGJ398 together with Dox. Similar results were obtained when an overexpressed pFGFR2a was knocked down by corresponding siRNA before Dox (Eto) exposure. Moreover, FGFR inhibition/depletion caused a loss of Rad51 foci in Dox-treated GIST cells, suggesting that FGFR-signaling plays an important regulatory role in homology-mediated DNA repair. Our data show that combined therapy (RTKs inhibitors supplemented with low doses of topoisomerase II inhibitors) might be effective for unresectable and metastatic forms of GISTs. In case of resistance to IM because of RTKs switch indicated above, FGFR inhibitors (e.g. BGJ398) might be potentially useful because of their ability to sensitize tumor cells to topoisomerase II inhibitors and induce tumor cell apoptosis by targeting DNA double-strand breaks repair.

https://ift.tt/2rR3byQ

Generation and characterization of a paclitaxel-resistant human gastric carcinoma cell line

The main aim of this study was to establish a novel paclitaxel (PTX)-resistant human gastric carcinoma cell line and to investigate its biological significance. A cell line, MGC803/PTX, was established by gradually increasing PTX density on the basis of MGC803 over a period of 10 months. In addition, a pair of resistant cell lines (SW620 and SW620/PTX) were added to further explain the resistant mechanism of PTX. The drug resistance index and stability of MGC803/PTX cells were detected using the Cell Counting Kit-8 method. The morphological features were observed using inverted microscopy. Apoptosis was measured by flow cytometry (FCM) and Hoechst 33258 fluorescence staining. The distribution of the cell cycle was determined by FCM, and protein expressions of P-gp, Bcl-2, Bax, and PARP were detected by western blot analysis. When characterizing the resistance in vitro, we found that MGC803/PTX cells were 10.3-fold more resistant to PTX compared with MGC803 cells. In addition, MGC803/PTX cells showed cross-resistance to 5-fluorouracil and adriamycin. FCM and Hoechst 33258 fluorescence staining indicated that MGC803/PTX cells had a significantly lower percentage of apoptotic cells after treatment with PTX compared with MGC803 cells. Other differences between parental cells and resistant cells included morphology, proliferation rate, doubling time, cell cycle distribution, and colony-formation rate. Western blot analysis indicated that P-gp, Bcl-2, and PARP protein were more abundant in MGC803/PTX and SW620/PTX cells compared with MGC803 and SW620 cells, whereas Bax protein levels were lower in resistant cells. Furthermore, MGC803/PTX cells showed obvious resistance to PTX in vivo. To our knowledge, this is the first report on the establishment of a PTX-resistant MGC803 cell line, which is an important tool to explore the resistance of anticancer drugs and to overcome tumor drug resistance.

https://ift.tt/2Iwh2Rj

Real-world healthcare costs of ipilimumab in patients with advanced cutaneous melanoma in The Netherlands

There is limited evidence on the costs associated with ipilimumab. We investigated healthcare costs of all Dutch patients with advanced cutaneous melanoma who were treated with ipilimumab. Data were retrieved from the nation-wide Dutch Melanoma Treatment Registry. Costs were determined by applying unit costs to individual patient resource use. A total of 807 patients who were diagnosed between July 2012 and July 2015 received ipilimumab in Dutch practice. The mean (median) episode duration was 6.27 (4.61) months (computed from the start of ipilimumab until the start of a next treatment, death, or the last date of follow-up). The average total healthcare costs amounted to €81 484, but varied widely (range: €18 131–€160 002). Ipilimumab was by far the most important cost driver (€73 739). Other costs were related to hospital admissions (€3323), hospital visits (€1791), diagnostics and imaging (€1505), radiotherapy (€828), and surgery (€297). Monthly costs for resource use other than ipilimumab were €1997 (SD: €2629). Treatment-naive patients (n=344) had higher total costs compared with previously-treated patients (n=463; €85 081 vs. €78 811). Although patients with colitis (n=106) had higher costs for resource use other than ipilimumab (€11 426) compared with patients with other types of immune-related adverse events (n=90; €9850) and patients with no immune-related adverse event (n=611; €6796), they had lower total costs (€76 075 vs. €87 882 and €81 480, respectively). In conclusion, this nation-wide study provides valuable insights into the healthcare costs of advanced cutaneous melanoma patients who were treated with ipilimumab in clinical practice. Most of the costs were attributable to ipilimumab, but the costs and its distribution varied considerably across subgroups.

https://ift.tt/2rVb723

Antineoplastic activity of linear leucine homodipeptides and their potential mechanisms of action

Galaxamide is a rare cyclic homopentapeptide composed of three leucines and two N-methyl leucines isolated from marine algae Galaxaura filamentosa. The strong antitumor activity of this compound makes it a promising candidate for tumor therapy. The synthesis of galaxamide, however, is a complex process, and it has poor water solubility. On the basis of its special chemical composition, we designed a series of linear leucine homopeptides. Among seven dipeptide derivatives, five compounds with terminal protection groups and methyl substitution of the hydrogen in the amido group showed remarkable inhibitory effects against various cancer cells. N-tertbutyl-D-leucine-N-methyl-D-leucinebenzyl (A7), the only stereomer condensed by two D-leucines, showed the highest antineoplastic activity. A7-treated cells showed cell cycle arrest and morphological changes typical of cells undergoing apoptosis. The population of Annexin-V positive/propidium iodide-negative cells also increased, indicating the induction of early apoptosis. A7 promoted the cleavage of caspase-9 and caspase-3, as well as increased intracellular Ca2+ levels and decreased the mitochondrial membrane potential. Collectively, certain linear leucine dipeptides derived from cyclic pentapeptide are able to inhibit tumor cell proliferation through cell cycle arrest and apoptosis induction. The N-methyl group in the side chain and the D/L conformation of the amino-acid residue are critical for their activity.

https://ift.tt/2GxyDXc

Presurgical pazopanib for renal cell carcinoma with inferior vena caval thrombus: a single-institution study

The aim of this study was to investigate the clinical benefit of presurgical therapy with pazopanib in renal cell carcinoma (RCC) patients with a tumor thrombus extending to a high level in the vena cava. A retrospective review was performed for seven consecutive patients with RCC and tumor thrombus involving the vena cava above the hepatic vein (level 3–4, Mayo Clinic classification) treated with pazopanib without initial cytoreductive nephrectomy at our institution. The effect of pazopanib was assessed in terms of the primary site response, thrombus diameter, and height (before and after treatment) on computed tomography or MRI. The tumor thrombus level before the induction of pazopanib was 3 in one patient and 4 in the remaining six patients. After pazopanib, shrinkage of the primary site and thrombus diameter and length were observed in all patients except one (with a rhabdoid tumor). The mean decreases of primary tumor diameter, tumor thrombus diameter, and length were 14, 9, and 31 mm, respectively. The tumor thrombus level decreased in three (43%) patients and remained stable in the remaining patient. Our findings suggest that presurgical treatment with pazopanib may shrink the tumor thrombus and decrease the surgical invasiveness in RCC patients with a high-level tumor thrombus.

https://ift.tt/2IS1MS8

Inhibition of anaplastic lymphoma kinase promotes apoptosis and suppresses proliferation in human hepatocellular carcinoma

Our study was to examine the roles of crizotinib and ceritinib in hepatocellular carcinoma (HCC) cells and explore the possible mechanisms. MTT assay was employed to examine the proliferation of five HCC cell lines treated with various concentrations of crizotinib or ceritinib. HepG2 and HCCLM3 cells were incubated with 2 nmol/l ceritinib for 1 week, followed by crystal violet staining and cell counting. Protein amounts of t-ALK, p-ALK, t-AKT, p-AKT, t-ERK, p-ERK, Mcl-1, survivin, and XIAP in HepG2 cells under different culture conditions were evaluated by western blot. HepG2 and HCCLM3 cells were treated with vehicle or ceritinib and measured by flow cytometry apoptosis analysis with Annexin-V/propidium iodide staining. MTT assay showed that both crizotinib and ceritinib suppressed the proliferation of various human HCC cells. Crystal violet staining analysis also indicated that ceritinib effectively inhibited human HCC cell proliferation. Western blot analysis indicated that both crizotinib and ceritinib inhibited ALK, AKT, and ERK phosphorylations. In addition, ceritinib reduced antiapoptotic gene expressions in HepG2 cells. Flow cytometry analysis indicated that ceritinib induced HepG2 and HCCLM3 cells apoptosis. ALK inhibitor exhibited antitumor effects by inhibiting ALK activation, repressing AKT and ERK pathways, and suppressing antiapoptotic gene expressions, which subsequently promoted apoptosis and suppressed HCC cell proliferations.

https://ift.tt/2GwS42x

Thyroid cancer management: from a suspicious nodule to targeted therapy

Thyroid nodules are very common, and their frequency is four to five times higher in women than in men. Most of them are benign, with only a very little percentage revealing a malignant neoplasm. About 50% of thyroid nodules are detected by self-palpation of neck, whereas the other 50% are diagnosed by neck ultrasonography and following fine-needle aspiration. Management of thyroid nodules is very difficult, because benign nodules are prevalent, whereas thyroid carcinoma is uncommon, representing only 1% of all malignancies. A standard diagnostic approach is represented by 'first-level' exams, consisting in neck ultrasonography and serum thyroid-stimulating hormone measurement, followed, only for nodules that are suspicious of malignancy, by 'second-level' exams, consisting of fine-needle aspiration and mutational test, which does detect particular DNA mutations present only in malignant cells. In this review, we will analyze the genetics of thyroid cancer and its heterogeneity, and we will briefly describe the current available diagnostic and therapeutic approaches.

https://ift.tt/2IS1Lh2

Conjugation with polyamines enhances the antitumor activity of naphthoquinones against human glioblastoma cells

Glioblastoma multiform (GBM) is the most common and devastating type of primary brain tumor, being considered the deadliest of human cancers. In this context, extensive efforts have been undertaken to develop new drugs that exhibit both antiproliferation and antimetastasis effects on GBM. 1,4-Naphthoquinone (1,4-NQ) scaffold has been found in compounds able to inhibit important biological targets associated with cancer, which includes DNA topoisomerase, Hsp90 and monoamine oxidase. Among potential antineoplastic 1,4-NQs is the plant-derived lapachol (2-hydroxy-3-prenyl-1,4-naphthoquinone) that was found to be active against the Walker-256 carcinoma and Yoshida sarcoma. In the present study, we examined the effect of polyamine (PA)-conjugated derivatives of lapachol, nor-lapachol and lawsone on the growth and invasion of the human GBM cells. The conjugation with PA (a spermidine analog) resulted in dose-dependent and time-dependent increase of cytotoxicity of the 1,4-NQs. In addition, in-vitro inhibition of GBM cell invasion by lapachol was increased upon PA conjugation. Previous biochemical experiments indicated that these PA-1,4-NQs are capable of inhibiting DNA human topoisomerase II-α (topo2α), a major enzyme involved in maintaining DNA topology. Herein, we applied molecular docking to investigate the binding of PA-1,4-NQs to the ATPase site of topo2α. The most active molecules preferentially bind at the ATP-binding site of topo2α, which is energetically favored by the conjugation with PA. Taken together, these findings suggested that the PA-1,4-NQ conjugates might represent potential molecules in the development of new drugs in chemotherapy for malignant brain tumors.

https://ift.tt/2GucKbu

Venous thromboembolic events in patients with lung cancer treated with cisplatin-based versus carboplatin/nedaplatin-based chemotherapy

An association between chemotherapy and venous thromboembolic events (VTEs) in patients with cancer is well established, with cisplatin (CDDP) being one of the most well-studied risk factors. However, whether CDDP is more strongly associated with occurrence of VTEs than carboplatin (CBDCA) or nedaplatin (CDGP) is controversial. Our purposes were to characterize patients with lung cancer and in-hospital VTEs, identify risk factors associated with VTEs, and compare the risks associated with CDDP-based versus CBDCA/CDGP-based chemotherapy. We retrospectively identified patients with lung cancer who underwent platinum-based chemotherapy from April 2012 to March 2015 from a national inpatient database in Japan. We used multivariable logistic regression analysis to analyze associations between various factors, including chemotherapy regimens and VTE. Of 235 104 eligible patients, 675 (0.29%) had VTEs after receiving platinum-based chemotherapy while hospitalized. Multivariable analysis showed that age, activity of daily living index, and invasive medical procedures were significant risk factors for the occurrence of VTE. Furthermore, CDDP-based chemotherapy was associated with a higher rate of VTE than CBDCA/CDGP-based chemotherapy (adjusted odds ratio: 1.35; 95% confidence interval: 1.08–1.68; P

https://ift.tt/2IU003c

Celastrol inhibits colorectal cancer cell proliferation and migration through suppression of MMP3 and MMP7 by the PI3K/AKT signaling pathway

Colorectal cancer (CRC) is one of the most frequent malignant tumors. Signaling by the PI3K/AKT pathway is crucial for CRC development and progression, including proliferation and migration. Celastrol has an anticancer effect, but its mechanism needs to be determined. Here, we showed that celastrol suppressed CRC cell proliferation and migration. Celastrol treatment also decreased the PI3K/AKT pathway components, and MMP3 and MMP7 expression levels. In addition, knockdown of AKT, not mTOR, inhibited MMP3 and MMP7 expression levels and AKT silencing promoted the celastrol-induced effects on CRC cell proliferation and migration. Taken together, these findings indicated that the celastrol-induced antitumor effects were mediated through MMP3 and MMP7 by the PI3K/AKT signaling pathway.

https://ift.tt/2IAAkFu

Real-world use, safety, and survival of ipilimumab in metastatic cutaneous melanoma in The Netherlands

Phase III trials with ipilimumab showed an improved survival in patients with metastatic melanoma. We evaluated the use and safety of ipilimumab, and the survival of all patients with metastatic cutaneous melanoma (N=807) receiving ipilimumab in real-world clinical practice in The Netherlands using data from the Dutch Melanoma Treatment Registry. Patients who were registered between July 2012 and July 2015 were included and analyzed according to their treatment status: treatment-naive (N=344) versus previously-treated (N=463). Overall, 70% of treatment-naive patients and 62% of previously-treated patients received all four planned doses of ipilimumab. Grade 3 and 4 immune-related adverse events occurred in 29% of treatment-naive patients and 21% of previously-treated patients. No treatment-related deaths occurred. Median time to first event was 5.4 months [95% confidence interval (CI): 4.7–6.5 months] in treatment-naive patients and 4.4 months (95% CI: 4.0–4.7 months) in previously-treated patients. Median overall survival was 14.3 months (95% CI: 11.6–16.7 months) in treatment-naive patients and 8.7 months (95% CI: 7.6–9.6 months) in previously-treated patients. In both patient groups, an elevated lactate dehydrogenase level (hazard ratio: 2.25 and 1.70 in treatment-naive and previously-treated patients, respectively) and American Joint Committee on Cancer M1c-stage disease (hazard ratio: 1.81 and 1.83, respectively) were negatively associated with overall survival. These real-world outcomes of ipilimumab slightly differed from outcomes in phase III trials. Although phase III trials are crucial for establishing efficacy, real-world data are of great added value enhancing the generalizability of outcomes of ipilimumab in clinical practice.

https://ift.tt/2IS1FWI

Differential microRNA profiles between fulvestrant-resistant and tamoxifen-resistant human breast cancer cells

Increasing evidence has shown that the dysregulation of microRNAs (miRNAs) is associated with drug resistance. Fulvestrant and tamoxifen represent the major endocrine drugs for the treatment of breast cancer patients, and yet little is known about the biological mechanisms of acquiring resistance to fulvestrant and tamoxifen, let alone the differences between cell lines resistant to these two drugs. Exploration of the differential miRNA profiles between these two cell lines is a useful way to further clarify these resistance mechanisms. The fulvestrant-resistant cell line (MCF7-F) and the tamoxifen-resistant cell line (MCF7-T) were established from the drug-sensitive parental MCF7 cell line using a 21-day high-dose antiestrogen induction method. Differentially expressed miRNA profiles of MCF7-F and MCF7-T were detected using microarray; then, multiple bioinformatic analyses were carried out, including protein–protein interaction network, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway analysis. Compared with the parental MCF7 cell line, more miRNAs were found to be participating in the process of acquiring fulvestrant resistance than tamoxifen resistance. miR-4532, miR-486-5p, miR-138, miR-1228, and miR-3178 could be new targets for combating both fulvestrant resistance and tamoxifen resistance. miR-3188, miR-21, miR-149, and others may be associated with fulvestrant resistance, whereas miR-342 and miR-1226 may be associated with tamoxifen resistance in breast cancer cells. We found differential miRNA profiles between fulvestrant-resistant and tamoxifen-resistant breast cancer cells, but the definite mechanism involved in gaining resistance still needs further study.

https://ift.tt/2Ixx4KX

Prolonged activity and toxicity of sirolimus in a patient with metastatic renal perivascular epithelioid cell tumor: a case report and literature review

Perivascular epithelioid cell tumor (PEComa) is a family of mesenchymal tumors. Conventional chemotherapy has little activity in this disease, but case reports are available on the activity of mammalian target of rapamycin inhibitors (e.g. sirolimus and temsirolimus). Pharmacokinetic assays of sirolimus are available as this drug has a precise therapeutic window and blood levels might be influenced by CYP3A4 polymorphisms and drug interactions. We report on a case of a patient with metastatic, progressive PEComa who started sirolimus at a dose of 5 mg/day with evidence of grade (G) 3 mucositis, G2 thrombocytopenia, and G1 leucopenia 10 days after the treatment started, in absence of concomitant medications or prohibited food assumption. Elevated sirolimus blood levels were detected (156.8 ng/ml). Sirolimus was stopped, and toxicity resolved in 5 weeks. Computed tomography scan 2 months after the treatment started showed a partial response (RECIST). After toxicity resolution, the patient restarted sirolimus at a dose of 1 mg/day, with blood levels in the range of 10–20 ng/ml. Tumor response was confirmed and maintained, and the patient is still under treatment 18 months later, with no additional adverse effects. Genetic analysis of five selected polymorphisms (rs2740574, rs776746, rs1128503, rs2032582, and rs1045642) in drug metabolism enzymes and transporters did not provide a clear explanation of the observed unusual pharmacokinetic. This case confirms the activity of mammalian target of rapamycin inhibitors in PEComa and strengthens the importance of pharmacokinetic drug blood levels monitoring in patients treated with sirolimus. In our patient, after dose adjustment, sirolimus could be restarted with a prolonged clinical benefit and no additional toxicity.

https://ift.tt/2rSEqSP

Defining Value of Cancer Therapeutics—A Health System Perspective

Abstract

Because of the rising costs of cancer care and ongoing challenges in ensuring access to quality care, there is an increasing need to prioritize spending and define the benefits of therapy in proportion to costs. The term "value" has gained favor as means to define the relative utility of a medical intervention in terms of benefits, risks, and financial costs, which in turn can help clinicians, patients, and policy makers prioritize "high-value" care. While numerous value concepts have been proposed, a comprehensive discussion of value initiatives along the care continuum is missing. In this Commentary, we propose a health system taxonomy of value initiatives in cancer care to discuss what the field needs to progress.

https://ift.tt/2IxoxeT

Biomarkers for Homologous Recombination Deficiency in Cancer

Abstract

Defective DNA repair is a common hallmark of cancer. Homologous recombination is a DNA repair pathway of clinical interest due to the sensitivity of homologous recombination-deficient cells to poly-ADP ribose polymerase (PARP) inhibitors. The measurement of homologous recombination deficiency (HRD) in cancer is therefore vital to the appropriate design of clinical trials incorporating PARP inhibitors. However, methods to identify HRD in tumors are varied and controversial. Understanding existing and new methods to measure HRD is important to their appropriate use in clinical trials and practice. The aim of this review is to summarize the biology and clinical validation of current methods to measure HRD, to aid decision-making for patient stratification and translational research in PARP inhibitor trials. We discuss the current clinical development of PARP inhibitors, along with established indicators for HRD such as germline BRCA1/2 mutation status and clinical response to platinum-based therapy. We then examine newer assays undergoing clinical validation, including 1) somatic mutations in homologous recombination genes, 2) "genomic scar" assays using array-based comparative genomic hybridization (aCGH), single nucleotide polymorphism (SNP) analysis or mutational signatures derived from next-generation sequencing, 3) transcriptional profiles of HRD, and 4) phenotypic or functional assays of protein expression and localization. We highlight the strengths and weaknesses of each of these assays, for consideration during the design of studies involving PARP inhibitors.

https://ift.tt/2GwIWuN

Tumor-Infiltrating Lymphocytes in Patients Receiving Trastuzumab/Pertuzumab-Based Chemotherapy: A TRYPHAENA Substudy

Abstract

Background

There is an urgent requirement to identify biomarkers to tailor treatment in human epidermal growth factor receptor 2 (HER2)–amplified early breast cancer treated with trastuzumab/pertuzumab-based chemotherapy.

Methods

Among the 225 patients randomly assigned to trastuzumab/pertuzumab concurrently or sequentially with an anthracycline-containing regimen or concurrently with an anthracycline-free regimen in the Tryphaena trial, we determined the percentage of tumor-infiltrating lymphocytes (TILs) at baseline in 213 patients, of which 126 demonstrated a pathological complete response (pCR; ypT0/is ypN0), with 28 demonstrating event-free survival (EFS) events. We investigated associations between baseline TIL percentage and either pCR or EFS after adjusting for clinicopathological characteristics using logistic and Cox regression models, respectively. To understand TIL biology, we evaluated associations between baseline TILs and baseline tumor gene expression data (800 gene set by NanoString) in a subset of 173 patients. All statistical tests were two-sided.

Results

Among the patients with measurable TILs at baseline, the median level was 14.1% (interquartile range = 7.1%–32.4%). After adjusting for clinicopathological characteristics, baseline percentage TIL was not associated with pCR (adjusted odds ratio [aOR] for every 10-percentage unit increase in TILs = 1.12, 95% confidence interval [CI] = 0.95 to 1.31, P = .17). At a median follow-up of 4.7 years, for every increase in baseline TILs of 10%, there was a 25% reduction in the hazard for an EFS event (aOR = 0.75, 95% CI = 0.56 to 1.00, P = .05) after adjusting for baseline clinicopathological characteristics and pCR. Additionally, genes associated with epithelial-mesenchymal transition, angiogenesis, and T-cell inhibition such as SNAIL1, ZEB1, NOTCH3, and B7-H3 were statistically significantly inversely correlated with percentage TIL.

Conclusions

Baseline TIL percentage provides independent prognostic information in patients treated with trastuzumab/pertuzumab-based neoadjuvant chemotherapy. However, further validation is required.

https://ift.tt/2rTxWTL

The Effects of Metformin and Weight Loss on Biomarkers Associated With Breast Cancer Outcomes

Abstract

Background

This study investigated the effects of metformin and weight loss on biomarkers associated with breast cancer prognosis.

Methods

Overweight/obese postmenopausal breast cancer survivors (n = 333) were randomly assigned to metformin vs placebo and to a weight loss intervention vs control (ie, usual care). The 2 × 2 factorial design allows a single randomized trial to investigate the effect of two factors and interactions between them. Outcomes were changes in fasting insulin, glucose, C-reactive protein (CRP), estradiol, testosterone, and sex-hormone binding globulin (SHBG). The trial was powered for a main effects analysis of metformin vs placebo and weight loss vs control. All tests of statistical significance were two-sided.

Results

A total of 313 women (94.0%) completed the six-month trial. High prescription adherence (ie, ≥80% of pills taken) ranged from 65.9% of participants in the metformin group to 81.3% of those in the placebo group (P < .002). Mean percent weight loss was statistically significantly higher in the weight loss group (–5.5%, 95% confidence interval [CI] = –6.3% to –4.8%) compared with the control group (–2.7%, 95% CI = –3.5% to –1.9%). Statistically significant group differences (ie, percent change in metformin group minus placebo group) were –7.9% (95% CI = –15.0% to –0.8%) for insulin, –10.0% (95% CI = –18.5% to –1.5%) for estradiol, –9.5% (95% CI = –15.2% to –3.8%) for testosterone, and 7.5% (95% CI = 2.4% to 12.6%) for SHBG. Statistically significant group differences (ie, percent change in weight loss group minus placebo group) were –12.5% (95% CI = –19.6% to –5.3%) for insulin and 5.3% (95% CI = 0.2% to 10.4%) for SHBG.

Conclusions

As adjuvant therapy, weight loss and metformin were found to be a safe combination strategy that modestly lowered estrogen levels and advantageously affected other biomarkers thought to be on the pathway for reducing breast cancer recurrence and mortality.

https://ift.tt/2GwIL2B

Novel Insights Into the Impact of Lifestyle-Based Weight Loss and Metformin on Obesity-Associated Biomarkers in Breast Cancer

Obesity is recognized as a potentially modifiable health condition that is often associated with an abnormal physiologic state that leads to insulin resistance (hyperinsulinemia, dysglycemia, and inflammation), altered adipokines (higher leptin and lower adiponectin), and sex hormones (higher estrogens, androgens, and testosterone), all of which may impact cancer (1–3). Numerous studies have found these obesity-related factors to be associated with worse breast cancer outcomes (4,5). Higher fasting insulin, for example, measured in nondiabetic breast cancer patients at the time of diagnosis, has been associated with worse distant disease–free survival and overall survival (hazard ratio [HR] = 2.05, 95% confidence interval [CI] = 1.16 to 3.62, and HR = 2.57; 95% CI = 1.18 to 5.59, respectively, for upper vs lower quartile) (4). Clinical trials evaluating the survival effects of pharmacologic therapies and lifestyle interventions that lead to improvements in obesity and/or its associated physiology are underway.

https://ift.tt/2rYIKjJ

Associations Between Prediagnostic Concentrations of Circulating Sex Steroid Hormones and Esophageal/Gastric Cardia Adenocarcinoma Among Men

Abstract

Background

Esophageal adenocarcinoma (EA) and gastric cardia adenocarcinoma (GCA) are characterized by a strong male predominance. Concentrations of sex steroid hormones have been hypothesized to explain this sex disparity. However, no prospective population-based study has examined sex steroid hormones in relation to EA/GCA risk. Thus, we investigated whether prediagnostic circulating sex steroid hormone concentrations were associated with EA/GCA in a nested case–control study drawn from participants in three prospective cohort studies.

Methods

Using gas chromatography–mass spectrometry (GC-MS) and electrochemiluminescence immunoassay, we quantitated sex steroid hormones and sex hormone binding globulin, respectively, in serum from 259 EA/GCA male case participants and 259 matched male control participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, and Cancer Prevention Study II Nutrition Cohort. Multivariable conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between circulating hormones and EA/GCA risk. All statistical tests were two-sided.

Results

Higher concentrations of dehydroepiandrosterone (DHEA) were associated with a 38% decreased risk of EA/GCA (OR per unit increase in log₂ DHEA = 0.62, 95% CI = 0.47 to 0.82, P_trend = .001). Higher estradiol concentrations were associated with a 34% reduced risk of EA/GCA (OR = 0.66, 95% CI = 0.45 to 0.98, P_trend = .05), and the association with free estradiol was similar. No other associations between baseline hormone concentrations and future EA/GCA risk were observed.

Conclusions

This study provides the first evidence that higher concentrations of circulating DHEA, estradiol, and free estradiol may be associated with lower risks of EA/GCA in men.

https://ift.tt/2Gu3X9j

Finding the Whey to Improve Surgical Outcomes: Perioperative Nutrition Screening and Intervention

No abstract available

https://ift.tt/2wVpQ1O

American Society for Enhanced Recovery and Perioperative Quality Initiative Joint Consensus Statement on Nutrition Screening and Therapy Within a Surgical Enhanced Recovery Pathway

Perioperative malnutrition has proven to be challenging to define, diagnose, and treat. Despite these challenges, it is well known that suboptimal nutritional status is a strong independent predictor of poor postoperative outcomes. Although perioperative caregivers consistently express recognition of the importance of nutrition screening and optimization in the perioperative period, implementation of evidence-based perioperative nutrition guidelines and pathways in the United States has been quite limited and needs to be addressed in surgery-focused recommendations. The second Perioperative Quality Initiative brought together a group of international experts with the objective of providing consensus recommendations on this important topic with the goal of (1) developing guidelines for screening of nutritional status to identify patients at risk for adverse outcomes due to malnutrition; (2) address optimal methods of providing nutritional support and optimizing nutrition status preoperatively; and (3) identifying when and how to optimize nutrition delivery in the postoperative period. Discussion led to strong recommendations for implementation of routine preoperative nutrition screening to identify patients in need of preoperative nutrition optimization. Postoperatively, nutrition delivery should be restarted immediately after surgery. The key role of oral nutrition supplements, enteral nutrition, and parenteral nutrition (implemented in that order) in most perioperative patients was advocated for with protein delivery being more important than total calorie delivery. Finally, the role of often-inadequate nutrition intake in the posthospital setting was discussed, and the role of postdischarge oral nutrition supplements was emphasized.

https://ift.tt/2Iu8kau

No Guts, No Recovery: A Rational Approach to Postoperative Gastrointestinal Dysfunction

No abstract available

https://ift.tt/2IsqQA6

American Society for Enhanced Recovery and Perioperative Quality Initiative Joint Consensus Statement on Postoperative Gastrointestinal Dysfunction Within an Enhanced Recovery Pathway for Elective Colorectal Surgery

The primary driver of length of stay after bowel surgery, particularly colorectal surgery, is the time to return of gastrointestinal (GI) function. Traditionally, delayed GI recovery was thought to be a routine and unavoidable consequence of surgery, but this has been shown to be false in the modern era owing to the proliferation of enhanced recovery protocols. However, impaired GI function is still common after colorectal surgery, and the current literature is ambiguous with regard to the definition of postoperative GI dysfunction (POGD), or what is typically referred to as ileus. This persistent ambiguity has impeded the ability to ascertain the true incidence of the condition and study it properly within a research setting. Furthermore, a rational and standardized approach to prevention and treatment of POGD is needed. The second Perioperative Quality Initiative brought together a group of international experts to review the published literature and provide consensus recommendations on this important topic with the goal to (1) develop a rational definition for POGD that can serve as a framework for clinical and research efforts; (2) critically review the evidence behind current prevention strategies and provide consensus recommendations; and (3) develop rational treatment strategies that take into account the wide spectrum of impaired GI function in the postoperative period.

https://ift.tt/2wRbbVB

American Society for Enhanced Recovery and Perioperative Quality Initiative Joint Consensus Statement on Patient-Reported Outcomes in an Enhanced Recovery Pathway

Patient-reported outcomes (PROs) are measures of health status that come directly from the patient. PROs are an underutilized tool in the perioperative setting. Enhanced recovery pathways (ERPs) have primarily focused on traditional measures of health care quality such as complications and hospital length of stay. These measures do not capture postdischarge outcomes that are meaningful to patients such as function or freedom from disability. PROs can be used to facilitate shared decisions between patients and providers before surgery and establish benchmark recovery goals after surgery. PROs can also be utilized in quality improvement initiatives and clinical research studies. An expert panel, the Perioperative Quality Initiative (POQI) workgroup, conducted an extensive literature review to determine best practices for the incorporation of PROs in an ERP. This international group of experienced clinicians from North America and Europe met at Stony Brook, NY, on December 2–3, 2016, to review the evidence supporting the use of PROs in the context of surgical recovery. A modified Delphi method was used to capture the collective expertise of a diverse group to answer clinical questions. During 3 plenary sessions, the POQI PRO subgroup presented clinical questions based on a literature review, presented evidenced-based answers to those questions, and developed recommendations which represented a consensus opinion regarding the use of PROs in the context of an ERP. The POQI workgroup identified key criteria to evaluate patient-reported outcome measures (PROMs) for their incorporation in an ERP. The POQI workgroup agreed on the following recommendations: (1) PROMs in the perioperative setting should be collected in the framework of physical, mental, and social domains. (2) These data should be collected preoperatively at baseline, during the immediate postoperative time period, and after hospital discharge. (3) In the immediate postoperative setting, we recommend using the Quality of Recovery-15 score. After discharge at 30 and 90 days, we recommend the use of the World Health Organization Disability Assessment Scale 2.0, or a tailored use of the Patient-Reported Outcomes Measurement Information System. (4) Future study that consistently applies PROMs in an ERP will define the role these measures will have evaluating quality and guiding clinical care. Consensus guidelines regarding the incorporation of PRO measures in an ERP were created by the POQI workgroup. The inclusion of PROMs with traditional measures of health care quality after surgery provides an opportunity to improve clinical care.

https://ift.tt/2Kzq7cS

Pathologic complete response after gemcitabine and S-1 chemotherapy for far advanced intrahepatic cholangiocarcinoma

Abstract

We report the case of a 72-year-old man who was initially diagnosed with far advanced intrahepatic cholangiocarcinoma, associated with bulky lymph node metastasis involving the common hepatic artery and moderate amount of ascites around the liver. After 10 cycles of systemic chemotherapy combining gemcitabine and S-1 with well-tolerated toxicities, a CT scan showed a marked shrinkage of the liver mass and lymph nodes (clinical partial response) with disappearance of ascites, which could permit a radical resection of the tumor. He underwent left lobectomy of the liver with lymph node dissection, and histopathological examination revealed pathologic complete response. Seven years after surgery, he is in a good overall condition.

https://ift.tt/2LcRydF

A Prospective Observational Study of Breast Lumps in Adolescent Girls: Tertiary Care South Indian Teaching Hospital Experience

Abstract

The aim of the current study was to assess the incidence and varying clinical presentations of benign breast lumps in adolescent age group in a Tertiary care Medical College Hospital. This was a prospective, observational study of 6-year duration (2011 to 2017) conducted in a Medical College, South India. All adolescent age group patients visiting the outpatient department (OPD) with complaints of breast lump were enrolled into the study. Triple assessment comprising of clinical examination, imaging, and core biopsy was used for diagnosis and identification of type of tumor. Management of tumors was based on pathology of core biopsy. During the study duration (2011 to 2017), a total of 15 pediatric patients of age between 11 to 14 years, presented with complaints of breast lumps. The most common symptom included painless lump in breast in 11 patients (73.34%). The histopathological examination (HPE) reported 12 cases (80%) as fibroadenomas and only 3 cases (20%) were phyllodes tumors. Based on the results of HPE, majority of the patients (53.34%) underwent circumareolar cosmetic incision. The most common lesions in pediatric age group are benign fibroadenomas; however, phyllodes are also not rare, and to manage them appropriately, they should be diagnosed preoperatively with core biopsy. Cases of malignancy, including phyllodes tumors, ductal adenocarcinomas, and metastatic lesions, have been documented in children and adolescents. Therefore, malignancy should be considered in the diagnosis of a pediatric and adolescent breast mass until formally ruled out.

https://ift.tt/2k7RjUJ

Vasoformative Lesions in Mediastinal Mixed Germ Cell Tumors: an Interesting Account of Two Cases Spanning the Benign to Malignant Spectrum

Abstract

Extragonadal germ cell tumors are most commonly encountered in the anterior mediastinum. The presence of sarcomatous malignancies in these tumors is a rare phenomenon that adversely impacts patient prognosis because of poor response to conventional cisplatin-based chemotherapy. Even more unusual is the presence of florid benign somatic proliferations that overshadow the germ cell component, often resulting in misdiagnosis and inappropriate management. Two young male patients aged 17 and 28 years respectively presented with mass in the anterior mediastinum. Histopathology of both cases revealed mixed germ cell tumor admixed with prominent vascular component. Interestingly, one case showed malignant vasoformative neoplasm (angiosarcoma) while in the other the vascular proliferation was of benign nature (venous hemangioma).

https://ift.tt/2rSEscF

Desmoplastic Fibroma of Bone: a Case Series and Review of Literature

Abstract

Desmoplastic fibroma is an uncommon locally aggressive benign tumor of the bone. Patients usually present with a long-standing history of pain and swelling. Radiologically and histologically, it can mimic a variety of tumors. This article presents a report on three cases of desmoplastic fibroma in the proximal humerus, distal femur, and neck femur region. The varied radiographic features and the management of the three cases are described in detail. All the three patients were treated by extended curettage. Follow-up ranged from 2 to 5 years. There were no local or systemic recurrence until the last follow-up. Tumor resection with adequate margins is the preferred treatment, although extended curettage can be an acceptable alternative treatment modality when resection is not possible or acceptable.

https://ift.tt/2k7Gn9N

Physician assessed and patient reported urinary morbidity after radio-chemotherapy and image guided adaptive brachytherapy for locally advanced cervical cancer

The EMBRACE study is a prospective multi-institutional study on MRI guided adaptive brachytherapy (IGABT) in locally advanced cervix cancer (LACC). This analysis describes early to late urinary morbidity assessed by physicians and patients (PRO).

https://ift.tt/2rSk10b

Randomized trial comparing two methods of re-irradiation after salvage surgery in head and neck squamous cell carcinoma: Once daily split-course radiotherapy with concomitant chemotherapy or twice daily radiotherapy with cetuximab

A previous randomized trial in recurrent Head and Neck squamous-cell carcinoma (HNSCC) has shown re-irradiation combined with chemotherapy after salvage surgery significantly improved disease-free survival (DFS). The objective of this randomized trial was to compare two methods of re-irradiation in terms of toxicity and survival.

https://ift.tt/2wTOe3P

A radiosensitivity gene signature and PD-L1 predict the clinical outcomes of patients with lower grade glioma in TCGA

Identifying predictive factors for the clinical outcome of patients with lower grade gliomas following radiotherapy could help optimize patient treatments. Here, we investigate the predictive efficacy of both a previously identified "31-gene signature" and programmed death ligand-1 (PD-L1) expression.

https://ift.tt/2IvYDrW

Regulation of the oxidative balance with coenzyme Q10 sensitizes human glioblastoma cells to radiation and temozolomide

To investigate how the modulation of the oxidative balance affects cytotoxic therapies in glioblastoma, in vitro.

https://ift.tt/2GuSFll

Tracking tumor biology with radiomics: A systematic review utilizing a radiomics quality score

Introduction: In this review we describe recent developments in the field of radiomics along with current relevant literature linking it to tumor biology. We furthermore explore the methodologic quality of these studies with our in-house radiomics quality scoring (RQS) tool. Finally, we offer our vision on necessary future steps for the development of stable radiomic features and their links to tumor biology. Methods: Two authors (S.S. and H.W.) independently performed a thorough systematic literature search and outcome extraction to identify relevant studies published in MEDLINE/PubMed (National Center for Biotechnology Information, NCBI), EMBASE (Ovid) and Web of Science (WoS).

https://ift.tt/2IvYB3i

Heterogeneity Does Matter for Tumor Characterization

https://ift.tt/2k64gi2

Kein Nachweis einer reduzierten Spättoxizität durch Dosisreduktion im elektiven Lymphknotenbereich in der primären Radiochemotherapie von Kopf-Hals-Tumoren

https://ift.tt/2rV3iZd

Is ganglionated plexus ablation effective for treating atrial fibrillation?

Abstract

Purpose

Very few studies have investigated the efficacy of ganglionated plexus ablation during the conventional maze procedure. In this study, we sought to evaluate its additive effect in reducing recurrent atrial fibrillation after concomitant maze surgery.

Methods

A retrospective study was conducted of 79 patients who underwent Cox maze IV concomitantly with open-heart surgery with (GP group) or without (Maze group) ganglionated plexus mapping. All active ganglionated plexuses were ablated. The two groups were compared and their follow-up data were analyzed.

Results

Active ganglionated plexuses were found in 81% of patients who underwent ganglionated plexus mapping. The rates of freedom from atrial fibrillation at 1 year in the GP and Maze groups were 77 and 75%, respectively. The cumulative freedom from atrial fibrillation at follow-up (27.7 ± 17.3 months) was comparable in the two groups (p = 0.427). A multivariate analysis revealed that persistent atrial fibrillation for more than 90 months was an independent predictor of recurrent atrial fibrillation.

Conclusion

Ganglionated plexus ablation with Cox maze IV did not reduce the incidence of recurrent atrial fibrillation in comparison to Maze alone.

https://ift.tt/2Lf94hh

Systemic treatment of advanced non-small cell lung cancer: controversies and perspectives

Summary

Patients with advanced non-small cell lung cancer receive first-line therapy with chemotherapy, targeted therapies in case of tumors with driver mutations, and more recently also immune checkpoint inhibitors. Important controversies include the role of targeted therapies in combination with chemotherapy, optimal sequencing of treatments, treatment guidance by means of predictive biomarkers, and value-based judgements of treatments.

https://ift.tt/2Is3D0E

Estrogen receptor positive breast tumors resist chemotherapy by the overexpression of P53 in Cancer Stem Cells

Publication date: Available online 17 May 2018
Source:Journal of the Egyptian National Cancer Institute
Author(s): Fatma Ashour, Mohammed H. Awwad, Hayam E.L. Sharawy, Mohamed Kamal
Background and ObjectivesBreast cancer (BC) is classified according to estrogen receptor (ER) status into ER⁺ and ER⁻ tumors. ER⁺ tumors have a worse response to chemotherapy compared to ER⁻ tumors. BCL-2, TP53, BAX and NF-ΚB are involved in drug resistance in the ER⁺ tumors. Recently it was shown that Cancer Stem Cells (CSCs) play an important role in drug resistance. In this study we tested the hypothesis that CSCs of the ER⁺ tumors resist drug through the overexpression of BCL-2, TP53, BAX and NF-ΚB.MethodsCSCs were isolated by anoikis resistance assay from MCF7 (ER⁺) and MDA-MB-231 (ER⁻) cell lines. Isolated CSCs were treated with doxorubicin (DOX) and the mRNA expression levels of BCL-2, TP53, BAX and NFKB were investigated by quantitative real time PCR (qPCR) with and without treatment.ResultsBCL-2, BAX and NF-ΚB showed decreased expression in MCF7 bulk cancer cells after DOX treatment whereas only BCL-2 and BAX showed decreased expression in MDA-MB-231 bulk cancer cells. Interestingly TP53 was the only gene showed a considerable increase in its expression in CSCs of the ER⁺ MCF7 cell line compared to bulk cancer cells. Moreover, TP53 was the only gene showing exceptionally higher level of expression in MCF7-CSCs compared to MDA-MB-231-CSCs.ConclusionOur results suggest that CSCs in the ER⁺ cells escape the effect of DOX treatment by the elevation of p53 expression.



https://ift.tt/2Izd9eq

Expression of truncated HER2 and its prognostic value in HER2-positive breast cancer patients

Publication date: Available online 17 May 2018
Source:Journal of the Egyptian National Cancer Institute
Author(s): Alaa Mohamed Maria, Mohamed El-Shebiney, Ayman Mohamed El-Saka, Yomna Zamzam
PurposeThe purpose of this work was to assess the truncated form of human epidermal growth factor receptor 2 (HER2) such as p95-HER2 expression in HER2-positive breast cancer (BC) patients who developed metastatic disease after adjuvant treatment with a trastuzumab-containing regimen.Patients and methodsThirty-two histologically diagnosed HER2-positive BC patients who developed distant failure after treatment with trastuzumab-based chemotherapy (CT) regimen as an adjuvant therapy were included in the study. Immunohistochemistry (IHC) method was used to analyze p95-HER2 expression in the formalin-fixed, paraffin-embedded (FFPE) blocks of the enrolled patients.Resultsp95-HER2 was positive in 34.4% of the patients. The median overall survival (OS) was 22.5 and 35 months for p95-HER2 positive and negative patients, respectively (p = 0.036) and the median time to metastases was 14 and 21 months, respectively (p = 0.006). There was a statistically significant association between positive p95-HER2 expression and negative hormonal receptors expression (p = 0.004), high Ki-67 expression (p < 0.001) and development of visceral metastasis (p = 0.034).ConclusionExpression of p95-HER2 in HER2-positive BC patients is significantly associated with negative hormonal receptors expression, high Ki-67 expression, presence of visceral metastases and worse overall survival. A larger study is required to confirm its association with different prognostic factors and its effect on survival.



https://ift.tt/2L7OVK9

Endometrial carcinoma in a single horn of a bicornuate uterus: A case report

Publication date: Available online 17 May 2018
Source:Journal of the Egyptian National Cancer Institute
Author(s): Khaled Gaballa, Carla Cicero, Valerio Gallotta, Gianfranco Zannoni, Giovanni Scambia
We discuss the diagnosis and the management of endometrial carcinoma in a single horn of bicornuate uterus in a 64-year-old woman as a case report. The case underwent laparoscopic radical hysterectomy and bilateral iliac lymphadenectomy.The gross examination of the uterus revealed a bicornuate uterus with a greater horn of 12 × 9 × 8 cm and a smaller horn of 10 × 3 cm. The cavity of the greater horn showed a neoplastic growth of 10 cm with infiltration of about 1,8 cm of the myometrium from whole thickness of 1.9 cm. while the other horn was free of tumor tissue.The microscopic examination of the uterus revealed G2 endometrioid adenocarcinoma of the endometrium of the greater horn with infiltration of more than 50% of the myometrium.In the presence of bicornuate uterus, a bilateral endometrial biopsy should be performed in order to reduce the risk of delayed or missed diagnosis.The management of a case of bicornuate unicollis uterus with endometrial carcinoma in only one horn is the same as patients with endometrial cancer in single uterus and depends mainly on stage and histological grade of the tumor.The possibility of existence of a separate uterine cavity should always be considered when endometrial cancer is clinically suspected but pathology fails to confirm the diagnosis. This points out the importance of a careful physical examination and radiographic evaluation in such cases.



https://ift.tt/2KCqZNE

LncRNA TUG1 promoted KIAA1199 expression via miR-600 to accelerate cell metastasis and epithelial-mesenchymal transition in colorectal cancer

Abstract

Background

LncRNA TUG1 has been reported to be highly expressed in CRC samples and cells and promoted metastasis by affecting EMT, indicating a poor prognosis for colorectal cancer (CRC). In this study, we determined the underlying mechanism for tumor oncogenesis of lncRNA TUG1 in CRC metastasis.

Methods

The expressions of miR-600 and KIAA1199 in 76 CRC patients and CRC cells and CRC metastatic tissues were determined using qRT-PCR. Epithelial-mesenchymal transition (EMT)-related proteins were determined using western blot. CRC cell metastasis was assessed by colony formation, wound healing and transwell assay. Luciferase reporter gene assay was used to confirm miR-600 binding to KIAA1199 3'UTR.

Results

Our data showed that lncRNA TUG1 was upregulated in CRC cells, miR-600 was downregulated in CRC tissues, cell lines and CRC metastatic tissues, and low miR-600 expression predicted a poor clinical prognosis. Overexpression of miR-600 suppressed CRC cell migration/invasion and EMT-related proteins in vitro, inhibited tumor volume and weight, and decreased the number of CRC liver metastasis in vivo. KIAA1199 was upregulated in CRC tissues, and was negatively regulated by miR-600. KIAA1199 overexpression promoted CRC cell migration and invasion, which reversed the inhibition effect of miR-600 mimic on migration and invasion of CRC cells. Moreover, TUG1 negatively regulated miR-600, and inhibition of TUG1 suppressed CRC cell migration and invasion and EMT-related proteins via regulating miR-600.

Conclusion

Our study proved that TUG1 promoted KIAA1199 expression to accelerate EMT and metastasis of CRC cell through inhibition of miR-600 expression.

https://ift.tt/2rQTrV4

ADAM-17 is a poor prognostic indicator for patients with hilar cholangiocarcinoma and is regulated by FoxM1

Abstract

Background

A-disintegrin and metalloproteinases (ADAMs) are members of a family of multidomain transmembrane and secreted proteins. Specific ADAMs are upregulated in human cancers and correlated with tumor progression and poor outcome, but rarely studied in human hilar cholangiocarcinoma (HC). This study aimed to explore the expression profiles of ADAMs and their potential underlying mechanisms promoting cancer progression.

Methods

mRNA expression of ADAM-9, − 10, − 11, − 12, − 15, − 17, − 28, and − 33 was analyzed in human hilar cholangiocarcinoma (HC) samples. Immunohistochemical (IHC) analysis was used to detect the expression of ADAM-10, − 17, − 28, and FoxM1 in HC. The regulation of ADAM-17 by FoxM1 and their functional study was investigated in vivo and in vitro.

Results

ADAM-10, − 17, and − 28 were upregulated in tumors compared with matched non-cancerous tissues. IHC analysis revealed increased expression of ADAM-10, − 17, and − 28 in HC cells, and ADAM17 seems to be an independent prognostic factor. ADAM-17 is regulated by FoxM1. A decrease in the expression of ADAM-17 by silencing FoxM1 led to an inhibition of cell proliferation, tumor growth, and the production of tumor necrosis factor α. IHC analysis showed co-expression of FoxM1 and ADAM-17 in HC specimens.

Conclusions

The findings of the present study show an important role of the cross-talk among FoxM1, ADAM-17, and TNFa in HC development and progression.

https://ift.tt/2Gw4pUt

The clinical implications of G1-G6 transcriptomic signature and 5-gene score in Korean patients with hepatocellular carcinoma

Abstract

Background

Efforts have been made to classify Hepatocellular Carcinoma (HCC) at surgically curable stages because molecular classification, which is prognostically informative, can accurately identify patients in need of additional early therapeutic interventions. Recently, HCC classification based French studies on the expression of 16 genes and 5 genes were proposed. In 16-gene classification, transcriptomic signatures (G1-G6) were used to classify HCC patients into clinical, genomic and pathway-specific subgroups. In 5-gene score classification, the good or poor prognosis of HCC patients was predicted. The patient's cohort in these studies was mainly from Caucasian and African populations. Here, we aimed to validate G1-G6 and 5-gene score signatures in 205 Korean HCC patients since genomic profiles of Korean patients are distinct from other regions.

Methods

Integrated analyses using whole-exome sequencing, copy number variation and clinical data was performed against these two signatures to find statistical correlations. Kaplan-Meier, univariate and multivariate COX regression analysis were performed for Disease-Specific Survival (DSS) and Recurrence-Free Survival (RFS).

Results

The G2 and G3 subgroups of transcriptomic signature were significantly associated with TP53 mutations while G5 and G6 subgroups were significantly associated with CTNNB1 mutations which is in concordance with original French studies. Similarly, the poor prognosis group of 5-gene score showed shorter DSS (p = 0.045) and early RFS (p = 0.023) as well as a significant association with microvascular invasion, tumor size (> 5 cm), elevated AFP levels, and RB1 mutations. However, the 5-gene score was not an independent prognostic factor for survival.

Conclusion

The G1-G6 and 5-gene signatures showed significant concordance between genetic profiles of Korean HCC patients and patients in original French studies. Thus, G1-G6 and 5-gene score signatures can be targeted as potential therapeutic biomarkers against HCC patients worldwide.

https://ift.tt/2It7ivr

Risk factors for esophageal fistula in thoracic esophageal squamous cell carcinoma invading adjacent organs treated with definitive chemoradiotherapy: a monocentric case-control study

Abstract

Background

Standard treatment for unresectable esophageal squamous cell carcinoma (ESCC) without distant metastasis is definitive chemoradiotherapy (dCRT), in which the incidence of esophageal fistula (EF) is reported to be 10–12%. An ad hoc analysis of JCOG0303, a phase II/III trial of dCRT for patients with unresectable ESCC (including non-T4b), suggested that esophageal stenosis is a risk factor for EF. However, risk factors for EF in patients limited to T4b ESCC treated with dCRT have yet to be clarified. The aim of this study was to investigate risk factors for EF in T4b thoracic ESCC treated with dCRT.

Methods

We retrospectively analyzed the data of consecutive T4b thoracic ESCC patients who were treated with dCRT (cisplatin and fluorouracil) at Shizuoka Cancer Center between April 2004 and September 2015.

Results

Excluding 8 patients with esophageal fistula clearly attributable to other iatrogenic interventions, the data of 116 patients who met the inclusion criteria were analyzed. Esophageal fistula was observed in 28 patients (24%). Although the fistula was closed in 5 patients, overall survival was significantly shorter in patients who experienced esophageal fistula (8.0 vs. 26.8 months; p < 0.0001). Among four potential variables extracted in univariate analysis, namely, total circumferential lesion, elevated CRP level, elevated white blood cell count, and anemia, the first two were revealed as risk factors for esophageal fistula in multivariate analysis.

Conclusions

This study demonstrated that total circumferential lesion and CRP ≥1.00 mg/dL are risk factors for esophageal fistula in T4b thoracic ESCC treated with dCRT.

Trial registration

This study was retrospectively registered.

https://ift.tt/2GvIhKb

A computational study of hedgehog signalling involved in basal cell carcinoma reveals the potential and limitation of combination therapy

Abstract

Background

The smoothened (SMO) receptor is an essential component of the Sonic hedgehog (SHH) signalling, which is associated with the development of skin basal cell carcinoma (BCC). SMO inhibitors are indicated for BCC patients when surgical treatment or radiation therapy are not possible. Unfortunately, SMO inhibitors are not always well tolerated due to severe side effects, and their therapeutical success is limited by resistance mutations.

Methods

We investigated how common are resistance-causing mutations in two genomic databases which are not linked to BCC or other cancers, namely 1000 Genomes and ExAC. To examine the potential for combination therapy or other treatments, we further performed knowledge-based simulations of SHH signalling, in the presence or absence of SMO and PI3K/Akt inhibitors.

Results

The database analysis revealed that of 18 known mutations associated with Vismodegib-resistance, three were identified in the databases. Treatment of individuals carrying such mutations is thus liable to fail a priori. Analysis of the simulations suggested that a combined inhibition of SMO and the PI3K/Akt signalling pathway may provide an effective reduction in tumour proliferation. However, the inhibition dosage of SMO and PI3K/Akt depended on the activity of phosphodiesterases (PDEs). Under high PDEs activities, SMO became the most important control node of the network. By applying PDEs inhibition, the control potential of SMO decreased and PI3K appeared as a significant factor in controlling tumour proliferation.

Conclusions

Our systems biology approach employs knowledge-based computer simulations to help interpret the large amount of data available in public databases, and provides application-oriented solutions for improved cancer resistance treatments.

https://ift.tt/2rScS00

Increased systemic zonula occludens 1 associated with inflammation and independent biomarker in patients with hepatocellular carcinoma

Abstract

Background

Hepatocellular carcinoma (HCC) is a frequent type of primary liver cancer, and its prevalence is increasing worldwide. Indeed, the underlying molecular mechanism is not well understood. Previous studies have shown evidence that tight junction (TJ) components were correlated with carcinogenesis and tumor development. Our aims were to determine the serum levels of tight junction protein Zonula Occludens (ZO)-1 and an inflammatory marker such as high-sensitive C-reactive protein (hs-CRP) in HCC patients compared to healthy volunteers and also to identify the association between ZO-1 and inflammation in HCC.

Methods

Thirty HCC patients and 30 healthy volunteers were recruited in the current study. Clinical data regarding child class, BCLC staging, the number of lesions, tumor size, absence or presence of metastasis, cirrhosis and hepatitis infection were also collected in HCC patients. Plasma ZO-1 and serum hsCRP were analyzed by EIA and ELISA respectively and biochemical parameters by autoanalyser (AU680 Beckman Coulter, USA). Furthermore, hepatic ZO-1 protein expression and tissue localization were examined.

Results

Compared to healthy individuals, the serum levels of bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT) and alkaline phosphatase (ALP) were elevated significantly (P < 0.0001) whilst serum albumin level was significantly (P < 0.0001) decreased in HCC patients. Furthermore, tight junction protein ZO-1 concentration was significantly elevated in HCC patients compared to control subjects (648 ± 183.8 vs. 396.4 ± 135.8 pg/ml, respectively; P < 0.0001). Serum hsCRP level was also significantly increased in HCC patients compared to control subjects (17.25 ± 3.57 vs. 5.54 ± 2.62 mg/L, respectively; P < 0.0001). Moreover, decreased protein expression of ZO-1 was found in liver tissue obtained from HCC patients.

Conclusion

Our findings show for the first time that the systemic concentration of ZO-1 was significantly elevated in HCC patients and is positively correlated with inflammatory markers. Thus, the current study showing evidence that inflammation promotes plasma ZO-1 concentration and raises the possibility that it could be used as a potential diagnostic biomarker for HCC progression.

https://ift.tt/2wSofKi

DNA methylation signatures of breast cancer in peripheral T-cells

Abstract

Background

Immune surveillance acts as a defense mechanism in cancer, and its disruption is involved in cancer progression. DNA methylation reflects the phenotypic identity of cells and recent data suggested that DNA methylation profiles of T cells and peripheral blood mononuclear cells (PBMC) are altered in cancer progression.

Methods

We enrolled 19 females with stage 1 and 2, nine with stage 3 and 4 and 9 age matched healthy women. T cells were isolated from peripheral blood and extracted DNA was subjected to Illumina 450 K DNA methylation array analysis. Raw data was analyzed by BMIQ, ChAMP and ComBat followed by validation of identified genes by pyrosequencing.

Results

Analysis of data revealed ~ 10,000 sites that correlated with breast cancer progression and established a list of 89 CG sites that were highly correlated (p < 0.01, r > 0.7, r < − 0.7) with breast cancer progression. The vast majority of these sites were hypomethylated and enriched in genes with functions in the immune system.

Conclusions

The study points to the possibility of using DNA methylation signatures as a noninvasive method for early detection of breast cancer and its progression which need to be tested in clinical studies.

https://ift.tt/2rScRJu

Development of a normal tissue complication probability (NTCP) model for radiation-induced hypothyroidism in nasopharyngeal carcinoma patients

Abstract

Background

The objectives of this study were to build a normal tissue complication probability (NTCP) model of radiation-induced hypothyroidism (RHT) for nasopharyngeal carcinoma (NPC) patients and to compare it with other four published NTCP models to evaluate its efficacy.

Methods

Medical notes of 174 NPC patients after radiotherapy were reviewed. Biochemical hypothyroidism was defined as an elevated level of serum thyroid-stimulating hormone (TSH) value with a normal or decreased level of serum free thyroxine (fT4) after radiotherapy. Logistic regression with leave-one-out cross-validation was performed to establish the NTCP model. Model performance was evaluated and compared by the area under the receiver operating characteristic curve (AUC) in our NPC cohort.

Results

With a median follow-up of 24 months, 39 (22.4%) patients developed biochemical hypothyroidism. Gender, chemotherapy, the percentage thyroid volume receiving more than 50 Gy (V₅₀), and the maximum dose of the pituitary (P_max) were identified as the most predictive factors for RHT. A NTCP model based on these four parameters were developed. The model comparison was made in our NPC cohort and our NTCP model performed better in RHT prediction than the other four models.

Conclusions

This study developed a four-variable NTCP model for biochemical hypothyroidism in NPC patients post-radiotherapy. Our NTCP model for RHT presents a high prediction capability.

Trial registration

This is a retrospective study without registration.

https://ift.tt/2GvI0a7

Long-term familial Mediterranean fever remission on successful hepatitis C virus treatment in a patient not responding to colchicine: a case report

Familial Mediterranean fever is an autosomal recessive disorder characterized by periodic febrile attacks of aseptic serositis and/or arthritis. The main treatment is colchicine which prevents attacks in the m...

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In Response

No abstract available

https://ift.tt/2rQRo3l

Activation of Melatonin Receptors by Ramelteon Induces Cardioprotection by Postconditioning in the Rat Heart

Activation of melatonin receptors protects the heart against ischemia-reperfusion injury. Ramelteon, a clinically used drug for insomnia, acts via activation of melatonin receptors. We investigated whether ramelteon induces acute infarct size reduction by postconditioning. Male Wistar rats were randomized to 6 groups. Hearts were treated with melatonin and ramelteon at the beginning of reperfusion. The melatonin receptor inhibitor luzindole was administered with and without melatonin and ramelteon, respectively. Ramelteon reduced infarct size to the same extent as melatonin. Both effects were completely abolished by luzindole. The results show for the first time that ramelteon induces cardioprotection by postconditioning.

https://ift.tt/2GuF39Q

Finding the Whey to Improve Surgical Outcomes: Perioperative Nutrition Screening and Intervention

No abstract available

https://ift.tt/2wVpQ1O

World Health Organization-World Federation of Societies of Anaesthesiologists (WHO-WFSA) International Standards for a Safe Practice of Anesthesia

The International Standards for a Safe Practice of Anesthesia were developed on behalf of the World Federation of Societies of Anaesthesiologists (WFSA), a nonprofit organization representing anesthesiologists in 150 countries, and the World Health Organization (WHO). The recommendations have been approved by WHO and the membership of WFSA. These Standards are applicable to all anesthesia providers throughout the world. They are intended to provide guidance and assistance to anesthesia providers, their professional organizations, hospital and facility administrators, and governments for maintaining and improving the quality and safety of anesthesia care. The Standards cover professional aspects; facilities and equipment; medications and intravenous fluids; monitoring; and the conduct of anesthesia. HIGHLY RECOMMENDED standards, the functional equivalent of mandatory standards, include (amongst other things): the continuous presence of a trained and vigilant anesthesia provider; continuous monitoring of tissue oxygenation and perfusion by clinical observation and a pulse oximeter; intermittent monitoring of blood pressure; confirmation of correct placement of an endotracheal tube (if used) by auscultation and carbon dioxide detection; the use of the WHO Safe Surgery Checklist; and a system for transfer of care at the end of an anesthetic. The International Standards represent minimum standards and the goal should always be to practice to the highest possible standards, preferably exceeding the standards outlined in this document.

https://ift.tt/2rT1sJf

Enhanced Recovery After Surgery: Is It Time to Drive Patient-Reported Outcomes Through Robust Measurement?

No abstract available

https://ift.tt/2Iu8oqK

Textbook of Rapid Response Systems: Concept and Implementation, 2nd ed

No abstract available

https://ift.tt/2GuhEFz

Perioperative Nutrition: A High-Impact, Low-Risk, Low-Cost Intervention

No abstract available

https://ift.tt/2KDIai9

No Guts, No Recovery: A Rational Approach to Postoperative Gastrointestinal Dysfunction

No abstract available

https://ift.tt/2IsqQA6

Standardization of the Classification of Impaired Postoperative Gastric Function Within the Enhanced Recovery Pathways

No abstract available

https://ift.tt/2ITp5LE

Use of Regional Anesthesia for Outpatient Surgery Within the United States: A Prevalence Study Using a Nationwide Database

BACKGROUND: Regional anesthesia is of benefit for outpatient surgery given its demonstrated improvement in analgesia and decrease in complications, resulting in shorter average recovery room times and lower hospital readmission rates. Unfortunately, there are few epidemiological studies outlining the overall utilization of peripheral nerve blocks (PNBs) in this setting. Therefore, the primary objective of this study was to report the overall utilization of several types of PNBs among all candidate cases in the outpatient setting within the United States. METHODS: We identified all cases from the National Anesthesia Clinical Outcomes Registry that were performed as an outpatient surgery. We reported the frequency of various types of PNBs among all candidate cases, defined as cases that potentially could have received a PNB. Changes in prevalence of PNB utilization from 2010 to 2015 were analyzed by using logistic regression. RESULTS: Of the 12,911,056 outpatient surgeries in the National Anesthesia Clinical Outcomes Registry, 3,297,372 (25.5%) were amenable to a PNB. However, the overall PNB frequency was only 3.3% of the possible cases. The overall utilization for PNB of the brachial plexus, sciatic nerve, and femoral nerve were 6.1%, 1.5%, and 1.9%, respectively. The surgical procedures generating the highest volume of PNBs were shoulder arthroscopies and anterior cruciate ligament reconstruction, in which 41% and 32% received a PNB, respectively. During this time period, there was a significant increase in overall PNB utilization for both single-injection and continuous PNB (P

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Worldwide Standards of Practice for Anesthesia

No abstract available

https://ift.tt/2KykA6s

Is It Time to Reconsider the Concepts of “Universal Donor” and “ABO Compatible” Transfusions?

No abstract available

https://ift.tt/2Gxmguj

Old Ways Do Not Open New Doors: Norepinephrine for First-Line Treatment of Spinal Hypotension

No abstract available

https://ift.tt/2IN40m3

Can Lung Ultrasound Be the First-Line Tool for Evaluation of Intraoperative Hypoxemia?

No abstract available

https://ift.tt/2rSN83A

From Invention to Innovation: Bringing Perioperative Physiological Closed-Loop Systems to the Bedside

No abstract available

https://ift.tt/2wVpMPC

In Response

No abstract available

https://ift.tt/2Gu0bNt

By FAER Means or Foul: The Road to Advancement for the Academic Anesthesiologist

No abstract available

https://ift.tt/2IUcSXa

The Evolving Dilemma of Factor XI in Pregnancy: Suggestions for Management

A case of a patient with severe factor XI (FXI) deficiency who presented for her seventh labor and delivery is presented. The nature of FXI deficiency, its prevalence, and issues related to genetic screening are discussed. Published literature on the topic is reviewed, including criteria that were developed to assess bleeding, laboratory tools used to estimate bleeding risk, and available treatments. Within the context of this challenging clinical dilemma, specific recommendations are provided for the antepartum, intrapartum, and postpartum stages of pregnancy. These include recommendations that take into account both FXI levels and history of any abnormal bleeding. While there are effective treatments available, it is important to consider that institutional multidisciplinary protocols are needed to manage this complex disorder. More work is needed to define the best management protocols.

https://ift.tt/2IRiVvm

Myocardial Postconditioning by the Melatonin Receptor Agonist Ramelteon: Putting Pieces to the Puzzle

No abstract available

https://ift.tt/2wVpKHu

Summative Objective Structured Clinical Examination Assessment at the End of Anesthesia Residency for Perioperative Ultrasound

While standardized examinations and data from simulators and phantom models can assess knowledge and manual skills for ultrasound, an Objective Structured Clinical Examination (OSCE) could assess workflow understanding. We recruited 8 experts to develop an OSCE to assess workflow understanding in perioperative ultrasound. The experts used a binary grading system to score 19 graduating anesthesia residents at 6 stations. Overall average performance was 86.2%, and 3 stations had an acceptable internal reliability (Kuder–Richardson formula 20 coefficient >0.5). After refinement, this OSCE can be combined with standardized examinations and data from simulators and phantom models to assess proficiency in ultrasound.

https://ift.tt/2IyNxyt

Overexpression of ABCB4 contributes to acquired doxorubicin resistance in breast cancer cells in vitro

Abstract

Purpose

Doxorubicin is one of the most active agents in the first-line therapy for metastatic breast cancer, but its utility is partially limited by the frequent emergence of doxorubicin resistance. In this study, we aimed to investigate the role of ATP-binding cassette sub-family B, member 4 (ABCB4) in acquired doxorubicin resistance in breast cancer cells, as well as its potential mechanism.

Methods

In doxorubicin-sensitive and -resistant breast cancer cell lines MCF-7 and MDA-MB-231, the expression levels of ABCB4 were detected using real-time quantitative PCR and Western blot analysis, the DNA methylation and histone acetylation status of ABCB4 gene were investigated by bisulfite-sequencing PCR (BSP) and chromatin immunoprecipitation (ChIP) assays, and the doxorubicin sensitivity and intracellular doxorubicin accumulation were observed using cell cytotoxicity assay and flow cytometry. In Madin–Darby Canine Kidney (MDCKII) cells, In vitro transport assay was used to assess the ABCB4-mediated transport of doxorubicin.

Results

ABCB4 was overexpressed in doxorubicin-resistant breast cancer cells compared to their doxorubicin-sensitive counterparts, which was associated with reduced DNA methylation as well as increased histone acetylation at the ABCB4 promoter. ABCB4 could actively pump doxorubicin out of the cells, and knockdown of ABCB4 increased doxorubicin sensitivity and intracellular accumulation in doxorubicin-resistant breast cancer cells.

Conclusions

Our results indicate that ABCB4 is overexpressed in breast cancer cells with acquired doxorubicin resistance, which could be attributed, at least partially, to the epigenetic modifications of ABCB4 gene. ABCB4 mediates the efflux transport of doxorubicin, and contributes to the acquired resistance of doxorubicin in breast cancer cells.

https://ift.tt/2IAfq9v

Combination Glucose-Lowering Therapy Plans in T2DM: Case-Based Considerations

Abstract

Type 2 diabetes mellitus (T2DM) is a complex disease, and while lifestyle interventions remain the cornerstone of therapy, most patients will also require pharmacotherapy. Current diabetes treatment guidelines and algorithms recommend an individualized approach to setting glycemic goals and selecting treatment. Although a single antihyperglycemic agent may be appropriate as the initial T2DM pharmacotherapy, the progressive nature of the disease due to declining pancreatic β-cell function will result in the vast majority of T2DM patients eventually requiring two or more antihyperglycemic agents. The American Association of Clinical Endocrinologists/American College of Clinical Endocrinology T2DM management algorithm recommends initial dual agent combination therapy when a single agent is unlikely to achieve their target glycemia, i.e., for those patients with an HbA1c ≥ 7.5 and an individualized HbA1c target of < 7.5%. The American Diabetes Association Standards of Care recommend combination pharmacotherapy for those patients presenting with very elevated HbA1c levels (e.g., ≥ 9% and < 10%). Metformin (if well tolerated and not contraindicated) is the initial pharmacologic choice for most patients; selection of another antihyperglycemic agent to the regimen will depend on the presence of atherosclerotic cardiovascular disease and other patient-specific factors (e.g., age, known duration of T2DM, history of or risk for hypoglycemia and/or adverse consequences from hypoglycemia, other comorbidities, and available resources), along with drug-specific factors (e.g., risk for hypoglycemia, potential effects on weight, drug adverse event profiles, and cost). Combination therapy may be administered as a multi-pill regimen, a single-pill combination (i.e., fixed-dose combination oral therapy), or as a combination of oral and/or injectable therapies. This paper provides two illustrative case presentations to demonstrate how current treatment recommendations and algorithms can be used to guide the selection of non-insulin-based combination therapy for patients with T2DM in primary care settings and discusses the relative merits of several possible approaches for each patient.

Funding: Boehringer Ingelheim Pharmaceuticals, Inc.

https://ift.tt/2Gw8ckO