"p53 Polymorphism at Codon 72 and Breast Cancer" - Letter.

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"p53 Polymorphism at Codon 72 and Breast Cancer" - Letter.

J Cancer Prev. 2017 Mar;22(1):55

Authors: Afzaljavan F, Pasdar A

PMID: 28382287 [PubMed - in process]

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Non-homologous End Joining Inhibitor SCR-7 to Exacerbate Low-dose Doxorubicin Cytotoxicity in HeLa Cells.

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Non-homologous End Joining Inhibitor SCR-7 to Exacerbate Low-dose Doxorubicin Cytotoxicity in HeLa Cells.

J Cancer Prev. 2017 Mar;22(1):47-54

Authors: Kumar A, Bhatkar D, Jahagirdar D, Sharma NK

Abstract
Among the genotoxic drug regimens, doxorubicin (DOX) is known for its high-dose side effects in several carcinomas, including cervical cancer. This study reports on testing the combined use of a DOX genotoxic drug and SCR-7 non-homologous end joining (NHEJ) inhibitor for HeLa cells. An in vitro DNA damaging assay of DOX was performed on plasmid and genomic DNA substrate. In vitro cytotoxicity was investigated using trypan blue dye exclusion, DNA metabolizing, and propidium iodide-based flow cytometric assays. DOX (between 20-100 μM) displayed clear DNA binding and interaction, such as the shearing and smearing of plasmid and genomic DNA. DNA metabolizing assay data indicate that HeLa lysate with DOX and SCR-7 treatment exhibited better in vitro plasmid DNA stability compared with DOX treatment alone. SCR-7 augmented the effects of low-dose DOX by demonstrating enhanced cell death from 15% to 50%. The flow cytometric data also supported that the combination of SCR-7 with DOX lead to a 23% increase in propidium iodide-based HeLa staining, thus indicating enhanced death. In summary, the inhibition of NHEJ DNA repair pathway can potentiate low-dose DOX to produce appreciable cytotoxicity in HeLa cells.

PMID: 28382286 [PubMed - in process]

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Anti-proliferative Effects of Androctonus amoreuxi Scorpion and Cerastes cerastes Snake Venoms on Human Prostate Cancer Cells.

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Anti-proliferative Effects of Androctonus amoreuxi Scorpion and Cerastes cerastes Snake Venoms on Human Prostate Cancer Cells.

J Cancer Prev. 2017 Mar;22(1):40-46

Authors: Akef H, Kotb N, Abo-Elmatty D, Salem S

Abstract
The present study evaluated the effects of Androctonus amoreuxi scorpion venom, Cerastes cerastes snake venom and their mixture on prostate cancer cells (PC3). An MTT assay was used to determine the anti-proliferative effect of the venoms, while quantitative real time PCR was used to evaluate the expression of apoptosis-related genes (Bax and Bcl-2). Furthermore, colorimetric assays were used to measure the levels of malondialdehyde (MDA) and antioxidant enzymes. Our results show that the venoms significantly reduced PC3 cell viability in a dose-dependent manner. On the other hand, these venoms significantly decreased Bcl-2 gene expression. Additionally, C. cerastes venom significantly reduced Bax gene expression, while A. amoreuxi venom and a mixture of A. amoreuxi & C. cerastes venoms did not alter Bax expression. Consequently, these venoms significantly increased the Bax/Bcl-2 ratio and the oxidative stress biomarker MDA. Furthermore, these venoms also increased the activity levels of the antioxidant enzymes, catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase. Overall, the venoms have cytotoxic and anti-proliferative effects on PC3 cells.

PMID: 28382285 [PubMed - in process]

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Differential MicroRNA Expression Between Gastric Cancer Tissue and Non-cancerous Gastric Mucosa According to Helicobacter pylori Status.

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Differential MicroRNA Expression Between Gastric Cancer Tissue and Non-cancerous Gastric Mucosa According to Helicobacter pylori Status.

J Cancer Prev. 2017 Mar;22(1):33-39

Authors: Lee JW, Kim N, Park JH, Kim HJ, Chang H, Kim JM, Kim JW, Lee DH

Abstract
BACKGROUND: MicroRNAs (miRNAs) are key post-translational mechanisms which can regulate gene expression in gastric carcinogenesis. To identify miRNAs responsible for gastric carcinogenesis, we compared expression levels of miRNAs between gastric cancer tissue and non-cancerous gastric mucosa according to Helicobacter pylori status.
METHODS: Total RNA was extracted from the cancerous regions of formalin-fixed, paraffin-embedded tissues of H. pylori-positive (n = 8) or H. pylori-negative (n = 8) patients with an intestinal type of gastric cancer. RNA expression was analyzed using a 3,523 miRNA profiling microarray based on the Sanger miRBase. Validation analysis was performed using TaqMan miRNA assays for biopsy samples from 107 patients consisted of control and gastric cancer with or without H. pylori. And then, expression levels of miRNAs were compared according to subgroups.
RESULTS: A total of 156 miRNAs in the aberrant miRNA profiles across the miRNA microarray showed differential expression (at least a 2-fold change, P < 0.05) in cancer tissue, compared to noncancerous mucosa in both of H. pylori-negative and -positive samples. After 10 promising miRNAs were selected, validations by TaqMan miRNA assays confirmed that two miRNAs (hsa-miR-135b-5p and hsa-miR-196a-5p) were significantly increased and one miRNA (hsa-miR-145-5p) decreased in cancer tissue compared to non-cancerous gastric mucosa at H. pylori-negative group. For H. pylori-positive group, three miRNAs (hsa-miR-18a-5p, hsa-miR-135b-5p, and hsa-miR-196a-5p) were increased in cancer tissue. hsa-miR-135b-5p and hsa-miR-196a-5p were increased in gastric cancer in both of H. pylori-negative and -positive.
CONCLUSIONS: miRNA expression of the gastric cancer implies that different but partially common gastric cancer carcinogenic mechanisms might exist according to H. pylori status.

PMID: 28382284 [PubMed - in process]

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Protective Effect of White-fleshed Peach (Prunus persica (L.) Batsch) on Chronic Nicotine-induced Toxicity.

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Protective Effect of White-fleshed Peach (Prunus persica (L.) Batsch) on Chronic Nicotine-induced Toxicity.

J Cancer Prev. 2017 Mar;22(1):22-32

Authors: Kim HJ, Park KK, Chung WY, Lee SK, Kim KR

Abstract
BACKGROUND: Nicotine is a major toxic component of tobacco smoke and has been recognized as a risk factor to induce oxidative tissue damage, which is a precursor to cardiovascular diseases, lung-related diseases, and cancers. Peaches (Prunus persica) have been used for the treatment of degenerative disorders, such as hypermenorrhea, dysmenorrhea, and infertility in Asian countries. In this study, we investigated the effects of white-fleshed peach on the excretion of nicotine metabolites and 1-hydroxypyrene in smokers and chronic nicotine-induced tissue damages in mice.
METHODS: The concentrations of cotinine and 1-hydroxypyrene were measured in urine of smokers before or after intake of white-fleshed peaches. In addition, ICR mice were injected with nicotine (5 mg/kg body weight) and then orally administered with white-fleshed peach extracts (WFPE) (250 or 500 mg/kg body weight) for 36 days. The oxidative stress parameters and the activities of antioxidant enzymes were measured in liver and kidney tissues. Also, histological changes and nitrotyrosine expression were assessed.
RESULTS: Intake of white-fleshed peaches increased the urinary concentration of nicotine metabolites and 1-hydroxypyrene in 91.67% and 83.33% of smokers, respectively. WFPE decreased the malondialdehyde levels and recovered the activities of antioxidant enzymes in nicotine-injected mice. In addition, WFPE inhibited nitrotyrosine expression and inflammatory responses in the liver, kidney, and lung tissues of nicotine-treated mice.
CONCLUSIONS: White-fleshed peaches may increase the metabolism of toxic components in tobacco smoke in smokers and protect normal tissues against nicotine toxicity in mice. Therefore, supplementation of white-fleshed peaches might be beneficial to smokers.

PMID: 28382283 [PubMed - in process]

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Ursodeoxycholic Acid Induces Death Receptor-mediated Apoptosis in Prostate Cancer Cells.

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Ursodeoxycholic Acid Induces Death Receptor-mediated Apoptosis in Prostate Cancer Cells.

J Cancer Prev. 2017 Mar;22(1):16-21

Authors: Lee WS, Jung JH, Panchanathan R, Yun JW, Kim DH, Kim HJ, Kim GS, Ryu CH, Shin SC, Hong SC, Choi YH, Jung JM

Abstract
BACKGROUND: Bile acids have anti-cancer properties in a certain types of cancers. We determined anticancer activity and its underlying molecular mechanism of ursodeoxycholic acid (UDCA) in human DU145 prostate cancer cells.
METHODS: Cell viability was measured with an MTT assay. UDCA-induced apoptosis was determined with flow cytometric analysis. The expression levels of apoptosis-related signaling proteins were examined with Western blotting.
RESULTS: UDCA treatment significantly inhibited cell growth of DU145 in a dose-dependent manner. It induced cellular shrinkage and cytoplasmic blebs and accumulated the cells with sub-G1 DNA contents. Moreover, UDCA activated caspase 8, suggesting that UDCA-induced apoptosis is associated with extrinsic pathway. Consistent to this finding, UDCA increased the expressions of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor, death receptor 4 (DR4) and death receptor 5 (DR5), and TRAIL augmented the UDCA-induced cell death in DU145 cells. In addition, UDCA also increased the expressions of Bax and cytochrome c and decreased the expression of Bcl-xL in DU145 cells. This finding suggests that UDCA-induced apoptosis may be involved in intrinsic pathway.
CONCLUSIONS: UDCA induces apoptosis via extrinsic pathway as well as intrinsic pathway in DU145 prostate cancer cells. UDCA may be a promising anti-cancer agent against prostate cancer.

PMID: 28382282 [PubMed - in process]

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Predictive and Prognostic Biomarkers of Respiratory Diseases due to Particulate Matter Exposure.

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Predictive and Prognostic Biomarkers of Respiratory Diseases due to Particulate Matter Exposure.

J Cancer Prev. 2017 Mar;22(1):6-15

Authors: Kim HJ, Choi MG, Park MK, Seo YR

Abstract
Air pollution is getting severe and concerns about its toxicity effects on airway and lung disease are also increasing. Particulate matter (PM) is major component of air pollutant. It causes respiratory diseases, such as asthma, chronic obstructive pulmonary disease, lung cancer, and so on. PM particles enter the airway and lung by inhalation, causing damages to them. Especially, PM2.5 can penetrate into the alveolus and pass to the systemic circulation. It can affect the cardiopulmonary system and cause cardiopulmonary disorders. In this review, we focused on PM-inducing toxicity mechanisms in the framework of oxidative stress, inflammation, and epigenetic changes. We also reviewed its correlation with respiratory diseases. In addition, we reviewed biomarkers related to PM-induced respiratory diseases. These biomarkers might be used for disease prediction and early diagnosis. With recent trend of using genomic analysis tools in the field of toxicogenomics, respiratory disease biomarkers associated with PM will be continuously investigated. Effective biomarkers derived from earlier studies and further studies might be utilized to reduce respiratory diseases.

PMID: 28382281 [PubMed - in process]

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Anti-cancer Mechanism of Docosahexaenoic Acid in Pancreatic Carcinogenesis: A Mini-review.

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Anti-cancer Mechanism of Docosahexaenoic Acid in Pancreatic Carcinogenesis: A Mini-review.

J Cancer Prev. 2017 Mar;22(1):1-5

Authors: Park M, Kim H

Abstract
Pancreatic cancer is a highly aggressive malignant tumor of the digestive system and radical resection, which is available to very few patients, might be the only possibility for cure. Since therapeutic choices are limited at the advanced stage, prevention is more important for reducing incidence in high-risk individuals with family history of pancreatic cancer. Epidemiological studies have shown that a high consumption of fish oil or ω3-polyunsaturated fatty acids reduces the risk of pancreatic cancers. Dietary fish oil supplementation has shown to suppress pancreatic cancer development in animal models. Previous experimental studies revealed that several hallmarks of cancer involved in the pathogenesis of pancreatic cancer, such as the resistance to apoptosis, hyper-proliferation with abnormal Wnt/β-catenin signaling, expression of pro-angiogenic growth factors, and invasion. Docosahexaenoic acid (DHA) is a ω3-polyunsaturated fatty acid and rich in cold oceanic fish oil. DHA shows anti-cancer activity by inducing oxidative stress and apoptosis, inhibiting Wnt/β-catenin signaling, and decreasing extracellular matrix degradation and expression of pro-angiogenic factors in pancreatic cancer cells. This review will summarize anti-cancer mechanism of DHA in pancreatic carcinogenesis based on the recent studies.

PMID: 28382280 [PubMed - in process]

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Noninvasive characterization of pancreatic tumor mouse models using magnetic resonance imaging

Abstract

The preclinical models of pancreatic adenocarcinoma provide an alternative means for determining the mechanisms of malignancy and possibilities for treatments, thus representing a resource of immense potential for cancer treatment in medicine. To evaluate different tumor models, quantifiable magnetic resonance imaging (MRI) techniques can play a significant role in identifying valuable in vivo biomarkers of tumor characteristics. We characterized three models of pancreatic cancer with multiparametric MRI techniques. Tumor stromal density of each tumor was measured using diffusion-weighted imaging and magnetization transfer (MT-MRI). Histologic measurement showed a similar trend with tumor fibrosis levels. Results indicated that MRI measurements can serve as a valuable tool in identifying and evaluating tumor characteristics.

We characterized three mouse models of pancreatic ductal adenocarcinoma with noninvasive multiparametric magnetic resonance imaging (MRI). Tumor cellularity and stromal density of each tumor were investigated using diffusion-weighted MRI and magnetization transfer MRI, respectively. Histologic measurements showed a similar trend with tumor cellularity and fibrosis levels.

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Association of Tissue Abiraterone Levels and SLCO Genotype with Intraprostatic Steroids and Pathologic Response in Men with High-Risk Localized Prostate Cancer

Purpose: Germline variation in solute carrier organic anion (SLCO) genes influences cellular steroid uptake and is associated with prostate cancer (PCa) outcomes. We hypothesized that, due to its steroidal structure, the CYP17A inhibitor abiraterone may undergo SLCO-mediated transport and that SLCO gene variation may influence intracellular abiraterone levels and outcomes.<br /><br />Experimental Design: Steroid and abiraterone levels were measured by mass spectrometry in serum and tissue from 58 men with localized PCa in a clinical trial of LHRH agonist plus abiraterone acetate plus prednisone for 24 weeks prior to prostatectomy. Germline DNA was genotyped for 13 single nucleotide polymorphisms (SNPS) in 6 SLCO genes.<br /><br /> <p>Results:Abiraterone levels spanned a broad range (serum median 28ng/ml, 108nM; tissue median 77ng/ml, 271nM) and were correlated (r=0.355, p=0.001). Levels correlated positivey with steroids upstream of CYP17A (pregnenolone, progesterone), and inversely with steroids downstream of CYP17A (DHEA, AED, testosterone). Serum PSA and tumor volumes were higher in men with undetectable vs detectable tissue abiraterone at prostatectomy (median 0.10 vs 0.03ng/dl, p=0.02; 1.28 vs 0.44cc, p=0.09, respectively).  SNPs in SLCO2B1 associated with significant differences in tissue abiraterone (rs1789693, p=0.0008; rs12422149, p=0.03) and higher rates of minimal residual disease (tumor volume <0.5cc; rs1789693, 67% vs 27%, p=0.009; rs1077858, 46% vs 0%, p=0.03). LNCaP cells expressing SLCO2B1 showed 2-4 fold higher abiraterone levels compared to vector controls (p<0.05).</p> <p>Conclusions: Intraprostatic abiraterone levels and genetic variation in SLCO genes are associated with pathologic responses in high-risk localized PCa. Variation in SLCO genes may serve as predictors of response to abiraterone treatment.

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Epigenetic Regulation of KPC1 Ubiquitin Ligase Effects the NF-{kappa}B Pathway in Melanoma

Purpose: Abnormal activation of the NF-B pathway induces a more aggressive phenotype of cutaneous melanoma. Understanding the mechanisms involved in melanoma NF-B activation may identify novel targets for this pathway. KPC1, an E3 ubiquitin ligase, is a regulator of NF-B pathway. The objective of this study was to investigate the mechanisms regulating KPC1 expression and its clinical impact in melanoma. Experimental Design: The clinical impact of KPC1 expression and its epigenetic regulation were assessed in large cohorts of clinically well-annotated melanoma tissues (tissue micro-arrays; n=137, JWCI cohort; n=40) and The Cancer Genome Atlas database (TCGA cohort, n=370). Using melanoma cell lines, we investigated the functional interactions between KPC1 and NF-B, and the epigenetic regulations of KPC1, including DNA methylation and microRNA expression. Results: We verified that KPC1 suppresses melanoma proliferation by processing NF-B1 p105 into p50, thereby modulating NF-B-target gene expression. Concordantly, KPC1 expression was down-regulated in AJCC stage IV melanoma compared to early stages (stage I/II p=0.013, stage III p=0.004), and low KPC1 expression was significantly associated with poor overall survival in stage IV melanoma (n=137, Hazard Ratio 1.810, p=0.006). Furthermore, our data showed that high miR-155-5p expression, which is controlled by DNA methylation at its promoter region (TCGA; Pearson's r -0.455, p<0.001), is significantly associated with KPC1 down-regulation (JWCI; p=0.028, TCGA; p=0.003). Conclusions: This study revealed novel epigenetic regulation of KPC1 associated with NF-B pathway activation, promoting metastatic melanoma progression. These findings suggest the potential utility of KPC1 and its epigenetic regulation as theranostic targets.

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Critical depurinating DNA adducts: Estrogen adducts in the etiology and prevention of cancer and dopamine adducts in the etiology and prevention of Parkinson's disease

Abstract

Endogenous estrogens become carcinogens when dangerous metabolites, the catechol estrogen quinones, are formed. In particular, the catechol estrogen-3,4-quinones can react with DNA to produce an excess of specific depurinating estrogen-DNA adducts. Loss of these adducts leaves apurinic sites in the DNA, generating subsequent cancer-initiating mutations. Unbalanced estrogen metabolism yields excessive catechol estrogen-3,4-quinones, increasing formation of depurinating estrogen-DNA adducts and the risk of initiating cancer. Evidence for this mechanism of cancer initiation comes from various types of studies. High levels of depurinating estrogen-DNA adducts have been observed in women with breast, ovarian or thyroid cancer, as well as in men with prostate cancer or non-Hodgkin lymphoma. Observation of high levels of depurinating estrogen-DNA adducts in high risk women before the presence of breast cancer indicates that adduct formation is a critical factor in breast cancer initiation. Formation of analogous depurinating dopamine-DNA adducts is hypothesized to initiate Parkinson's disease by affecting dopaminergic neurons. Two dietary supplements, N-acetylcysteine and resveratrol complement each other in reducing formation of catechol estrogen-3,4-quinones and inhibiting formation of estrogen-DNA adducts in cultured human and mouse breast epithelial cells. They also inhibit malignant transformation of these cells. In addition, formation of adducts was reduced in women who followed a Healthy Breast Protocol that includes N-acetylcysteine and resveratrol. When initiation of cancer is blocked, promotion, progression and development of the disease cannot occur. These results suggest that reducing formation of depurinating estrogen-DNA adducts can reduce the risk of developing a variety of types of human cancer. This article is protected by copyright. All rights reserved.

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Low-dose total body irradiation: an overlooked cancer immunotherapy technique

Abstract

Low-dose total body irradiation (LD-TBI) has been shown to be an effective therapy for patients with hematologic malignancies. The application of this method has fallen out of favor as newer systemic therapies have been developed. Nevertheless, for management of many of these hematologic malignancies, no prospective randomized trial has shown that any other treatment is unequivocally superior to LD-TBI. The precise mechanism of action is uncertain but it is believed by some to be at least partly immunologically mediated. In this review, we shall discuss the clinical data on this method along with some new potential applications. We also discuss some of the potential immunological mechanisms behind LD-TBI and consider future possibilities.

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Validation of REM score to predict endometrial cancer in patients with ultrasound endometrial abnormalities: results of a new independent dataset

Abstract

The risk of endometrial malignancy (REM) score is a model formulated in a previous single-center validation study, which has been shown to predict endometrial cancer in women with ultrasound endometrial abnormalities based on multiple features (clinical, ultrasound and laboratorial). The purpose of this study was to validate the performance of REM score in an external validation setting. A population-based database with patients, who underwent elective hysteroscopy for ultrasound endometrial abnormalities between 2013 and 2016 at Department of Obstetrics and Gynecology of Campus Bio-medico of Rome, was used. Starting from January 2013 to June 2016, 330 patients were enrolled for hysteroscopy. Thirty-two patients were excluded due to Asherman syndrome or cervical stenosis. Therefore, a total of 298 patients were considered for the analysis. Based on pathologic examination, 102 patients were found to have endometrial cancer, and 196 had benign endometrial disease. Using the predefined cutoff of 0.3185, identified in the previous publication, in this independent cohort of patients we correctly classified 93/102 patients with endometrial cancer and 187/196 with benign disease, reporting an overall sensitivity and specificity of 93.9 and 95.4% (PPV = 0.91, NPV = 0.95), respectively. REM score showed a high positive predictive value for endometrial cancer prediction. However, before REM score can be applied in daily clinical practice, data from randomized controlled trials are needed.

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Dynamics of hormonal disorders following unilateral orchiectomy for a testicular tumor

Abstract

Testicular tumors and their treatment interfere with homeostasis, hormonal status included. The aim of the study was to evaluate hormonal disorders of the pituitary–gonadal axis in men treated for testicular tumors. One hundred twenty-eight men treated for a unilateral testicular tumor at our institution were included. The hormonal status was prospectively evaluated in 62 patients before orchiectomy, 120 patients 1 month after orchiectomy and 110 patients at least 1 year after the treatment. The concentrations of human chorionic gonadotropin (hCG), testosterone (T), estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin were measured. The clinically significant testosterone deficiency was defined either as testosterone <2.31 ng/mL or testosterone within the range of 2.31–3.46 ng/mL but simultaneous with T/LH ratio ≤1. Changes in hormone levels were significant: LH and FSH rose in the course of observation, and the concentration of hCG, testosterone, estradiol decreased. PRL concentration was the lowest at 1 month after orchiectomy. In multivariate analysis, the risk of the clinically significant testosterone deficiency was 0.2107 (95% CI 0.1206–0.3419) prior to orchiectomy, 0.3894 (95% CI 0.2983–0.4889) 1 month after surgery and 0.4972 (95% CI 0.3951–0.5995) 1 year after the treatment. The estradiol concentration was elevated in 40% of patients with recently diagnosed testicular cancer and that was correlated with a higher risk of testosterone deficiency after the treatment completion. Hormonal disorders of the pituitary–gonadal axis in men treated for testicular tumors are frequent. The malignant tissue triggers paraneoplastic disorders that additionally disturb the hormonal equilibrium.

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Targeted next-generation sequencing identified novel mutations in triple-negative myeloproliferative neoplasms

Abstract

Mutations in JAK2, MPL and CALR genes have been identified in the majority of myeloproliferative neoplasm (MPN) patients, and patients negative for these three mutations are the so-called triple-negative (TN) MPN. In this study, we examined the mutational profiles of 16 triple-negative MPN patients including 7 essential thrombocythemia (ET), 1 primary myelofibrosis and 8 polycythemia vera (PV). Targeted next-generation sequencing was performed using the ACTOnco Comprehensive Cancer Panel (Ion AmpliSeq Comprehensive Cancer Panel, Life Technologies) to target all coding exons of 409 cancer-related genes. Overall, 30 nonsynonymous somatic mutations were detected in 12 (75%) patients with a range of 1–5 mutations per sample. Notably, one ET patient was found to have JAK2V617F and KITP551L mutations at very low allele frequency. One MPLP70L and 1 MPLM602T mutations were identified each in 1 ET and 1 PV, respectively. Other recurrent mutations were also identified including KMT2C, KMT2D, IRS2, SYNE1, PDE4DIP, SETD2, ATM, TNFAIP3 and CCND2. In addition, germline mutations were also found in some cancer-related genes. Copy number changes were rare in this cohort of TN MPNs. In conclusion, both somatic and germline mutations can be detected in TN MPN patients.

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Metastasis: an early event in cancer progression

Abstract

Purpose

Metastasis is the leading cause of death for a majority of cancer patients, and thus the need to understand the biology of metastasis becomes increasingly acute. When metastasis is initiated in tumor progression remains obscure. Better understanding of mechanisms regulating acquisition of metastatic ability in tumor cells will provide novel therapeutic targets and prevention of metastasis in clinics accompanied with the treatment of the primary tumor might be helpful in reducing metastasis-related mortality.

Methods

A literature search was performed in multiple electronic databases. Research papers from clinical reports to experimental studies on metastasis were analyzed.

Results

The article discusses tumor heterogeneity and genomic instability in the context of metastasis and tumor cell dissemination. And then we review biological mechanism of metastasis at an early stage in both intracellular (CSCs and CTCs) and extracellular (microenvironment) context. Finally, current development of anti-metastatic therapies is summarized.

Conclusions

Metastasis could be initiated at an early point of tumor progression. Therefore, early intervention on metastasis should be applied among cancer patients in clinical settings.

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Uric acid as a novel biomarker for bone-marrow function and incipient hematopoietic reconstitution after aplasia in patients with hematologic malignancies

Abstract

Purpose

Prolonged aplasia and graft failure (GF) represent life-threatening complications after hematopoietic cell transplantation (HCT) requiring suitable biomarkers for early detection and differentiation between GF and poor graft function (PGF). Uric acid (UA) is a strong immunological danger signal.

Methods

Laboratory results were analyzed from patients undergoing either allogeneic or autologous HCT or induction chemotherapy for acute leukemia (n = 50 per group, n = 150 total).

Results

During therapy, UA levels declined from normal values to hypouricemic values (all p < 0.001). Alongside hematopoietic recovery, UA serum levels returned to baseline values. During aplasia, UA levels remained low and started steadily increasing (defined as >two consecutive days, median one 2-day increase) at a median of 1 day before rising leukocytes in allogeneic HCT (p = 0.01) and together with leukocytes in autologous HCT (median one 2-day increase). During induction chemotherapy, a UA increase was also observed alongside rising leukocytes/neutrophils but also several times during aplasia (median 3 increases). Most HCT patients had no detectable leukocytes during aplasia, while some leukocytes remained detectable after induction therapy. No increase in UA levels was observed without concomitant or subsequent rise of leukocytes.

Conclusions

Changes in UA serum levels can indicate incipient or remaining immunological activity after HCT or induction therapy. They may, therefore, help to differentiate between PGF and GF.

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The role of the general practitioner in cancer care: a survey of the patients’ perspective

Abstract

Purpose

Modern cancer care is provided in highly specialized structures as certificated centres and comprehensive cancer center, as well as specialized practices. In contrast, the position of the general practitioner (GP) is less well characterised and there is a lack of information about his importance in the care for cancer patients. The aim of our survey was to assess the role of GPs in German cancer care from patients' perspective.

Methods

In several steps we developed a standardized anonymous questionnaire in cooperation with the German Association of General Practitioners and the Federal Association of German Self-Help Groups. This questionnaire was used in a print and an online version and distributed by the self-help organizations to their members.

Results

Seven hundred and forty participants took part in the survey, 66.5% women and 30.1% men. 71% had visited the GP during cancer therapy and 34.5% discussed decisions concerning diagnostics and therapy with him. The most relevant reasons to visit the GP during cancer therapy were to get a blood test (63.3%), comorbidities (42.7%) and complaints and side effects (38.3%). For the latter, most often a detailed discussion ensued (57%), fooled by a prescription (37.7%). In 63.4% the GP offered support when patients had some questions or worries concerning their cancer. Yet, 17% of the patients reported that the GP did not try to help. 85.5% of the participants thought that it is important that their GP is informed about the therapy on a regular basis. For 77.0%, a simultaneous care provided by the GP is important or very important.

Conclusion

Our survey points to the importance of the GP during cancer therapy from the patient's point of view. Patients want their GP to take an active part in the cancer therapy. Furthermore, early integration of the GP may also enhance early integration of palliative care and also help family members and caregivers. A strategy to integrate GPs is the establishment of shared care models, in which GPs are supported by specialists and get additional training in cancer care.

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Alpha tocopherol transfer protein (αTTP) is expressed in endometrial carcinoma and is correlated with FIGO stage and 5-year survival

Abstract

Background

Increased oxidative stress plays an important role in cancer development. Vitamin E is considered a potent anti-oxidant and its transfer protein αTTP facilitates its cellular delivery. We hypothesize that αTTP could be present in and have an impact on endometrial cancer.

Materials and methods

Ishikawa endometrial cancer cells were treated with BSO and AAPH to mimick oxidative stress conditions. αTTP was detected by immunocytochemistry and western blot. αΤΤP expression was then assessed in 191 endometrioid endometrial carcinomas. Immunopositivity was correlated with grade, FIGO stage, and 5-year survival. Immuno-reactivity was assessed with a semi-quantitative score.

Results

AAPH- and BSO-induced αTTP expression in Ishikawa cells. Immunohistochemical assessment of the 191 endometrial cancer cases showed that αTTP expression correlated with FIGO stage (p = 0.014) but not with grade. Five-year survival was significantly better in cases of lower αTTP expression compared to cases with higher expression (p = 0.041).

Conclusions

The current results show that αTTP plays a role in endometrial carcinoma. Possibly endometrial cancer cells attempt to protect themselves from increasing oxidative stress by up-regulating αTTP. Selective molecular interventions targeting oxidative stress escape strategies, e.g., by overexpression of αTTP, could, therefore, allow oxidative stress to damage cancer cell membranes and thus restrict cancer progression.

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Undertreatment trend in elderly lung cancer patients in Brazil

Abstract

Purpose

Elderly patients with lung cancer tend to be undertreated in comparison to younger patients. The objective of this study is to compare treatment modalities offered to lung cancer patients from 70 years of age or more with patients under 70.

Methods

For this study, an analytical cross-sectional epidemiological study conducted with data from the Brazilian hospital-based cancer registries between the years 2000 and 2011. In addition, odds ratios (OR) were calculated, with a 95% confidence intervals (95% CI), in conjunction with the construction of a logistic regression model.

Results

By analyzing the records of 40,403 patients with lung cancer, we found that overall, patients from 70 years of age or more corresponded to 28.6% of the study population. Squamous cell carcinoma was the most common histological type among patients ≥70 years of age, whereas adenocarcinoma was the more prevalent type among younger patients. In comparison to younger patients, the older ones were treated less often (OR = 0.57; 95% CI: 0.52–0.62). Moreover, older patients were less likely to undergo surgery (OR = 0.69; 95% CI: 0.64–0.75), radiotherapy (OR = 0.86; 95% CI: 0.81–0.92), chemotherapy (OR = 0.61; 95% CI: 0.57–0.64), or an association of two or more treatment modalities (OR = 0.58; 95% CI: 0.54–0.62).

Conclusion

The study finds that Brazilian lung cancer patients ≥70 years of age are often undertreated and higher percentage of early death rates as compared to patients under 70. In regard to treatment, age alone should not determine whether patients with lung cancer are treated or not.

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Utility of the Ginza forceps for superficial phlebectomy during endovenous laser ablation of the great saphenous vein

Abstract

Purpose

To evaluate the efficiency of using the Ginza forceps (DVx, Tokyo, Japan), which have a long shaft and strong grip, for superficial phlebectomy with the stab avulsion technique, during simultaneous endovenous laser ablation (EVLA) of the great saphenous vein (GSV).

Methods

The subjects were patients treated with EVLA performed by a single operator at one institution. All patients had a GSV diameter of 4–10 mm and an EVLA length of the GSV of >20 cm. We compared 59 limbs treated only with the Varady hook (Group A) with 46 limbs treated with the Ginza forceps (Group G).

Results

The mean operative times for Groups A and G were 55.4 ± 17.1 vs. 48.5 ± 13.5 min, respectively (P = 0.002), and the number of stab incisions was 5.9 ± 2.9 (1–13) vs. 3.5 ± 2.3 (1–11), respectively (P < 0.001). The rates of nerve injury and thrombophlebitis were 1.7 vs. 0 and 3.4 vs. 0%, respectively.

Conclusions

Performing superficial phlebectomy with the Ginza forceps reduced the operation time and the number of stab wounds. These initial results suggest that using the Ginza forceps for the procedure is safe and efficient.

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International Cancer Education Conference 2016 Late-Breaking Abstracts

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Integrative transcriptome analysis of liver cancer profiles identifies upstream regulators and clinical significance of ACSM3 gene expression

Abstract

Purpose

Hepatocellular carcinoma (HCC) is one of the most common human malignancies. It has frequently been associated with metabolic perturbations and liver damages. Various members of the family of acyl-CoA synthetases are known to be involved in the production of bioactive fatty acids, and altered expression of its encoding genes has been found to be involved in metabolic perturbations. For the development of novel diagnostic and therapeutic HCC options, a fundamental understanding of the mechanisms associated with the deregulation of candidate genes involved in metabolic perturbation is required.

Methods

A meta-analysis of multiple HCC mRNA profiles was performed to identify consistently deregulated genes. Expression of the acyl-CoA synthetase medium chain family member 3 (ACSM3) gene was subsequently assessed in different HCC tumor stages and correlated with various clinicopathological features. Transcription regulation, survival and pathway-associated features of the ACSM3 gene were investigated using integrative functional genomic and molecular cell biological methods.

Results

We found that expression of the ACSM3 gene was significantly reduced in HCC tissues and was frequently downregulated in patients exhibiting high alpha-fetoprotein (AFP) levels, high alanine aminotransferase (ALT) levels, multiple nodules and large tumors. Loss of ACSM3 expression was found to correlate with advanced HCC stages and a poor survival. In addition, HNF4α was found to positively regulate the expression of the ACSM3 gene, while PPARγ was found to transcriptionally repress it. Downregulation of ACSM3 expression was perceived upon activation of the TGFβ, WNT, AKT and MYC signalling pathways. In addition, we found that ACSM3 expression correlates with fatty acid oxidation in HCC.

Conclusion

Our data provide evidence for a differential expression and regulation of the ACSM3 gene in HCC, and may lay a foundation for therapeutically targeting fatty acid metabolism in these tumors.

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Sleep-Disordered Breathing, Postoperative Delirium, and Cognitive Impairment.

Sleep-disordered breathing (SDB) is highly prevalent in the general population and has been associated with cognitive impairment in older individuals. Delirium is an acute decline in cognitive function and attention that often occurs after surgery, especially in older individuals. Several recent studies suggest an association between SDB and postoperative delirium. The aim of this systematic review is to examine the current literature on SDB, postoperative delirium, and cognitive impairment and to discuss the pathophysiology and perioperative considerations. A literature search was performed of Medline (1946-2016), Medline In-Process (June 2016), Embase (1947-2016), Cochrane Central Register of Controlled Trials (May 2016), and Cochrane Database of Systematic Reviews (2005 to June 2016). Inclusion criteria for studies were (1) polysomnography confirmed SDB; (2) postoperative delirium or cognitive impairment confirmed by a validated diagnostic tool; and (3) publications in the English language. All study designs including randomized controlled trials and observational studies were included. The literature search identified 2 studies on SDB and postoperative delirium, 15 studies on SDB and cognitive impairment, and 5 studies on the effect of continuous positive airway pressure on cognitive impairment and delirium in older individuals. SDB was associated with cognitive impairment, and this systematic review revealed that SDB may be a risk factor for postoperative delirium, especially in older individuals. Although the pathophysiology of SDB and postoperative delirium is unclear and effective treatments for SDB to reduce the incidence of delirium have not been studied extensively, preliminary evidence suggests that continuous positive airway pressure therapy may lower the risk of delirium. Health care professionals need to be aware that undiagnosed SDB may contribute to postoperative delirium. Preoperative screening for SDB and strategies to reduce the risk for postoperative delirium may be helpful in older individuals. Further studies are needed to clarify the relationship between SDB and postoperative delirium and elucidate the pathophysiology of postoperative delirium through SDB. (C) 2017 International Anesthesia Research Society

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Computational and In Vitro Experimental Investigation of Intrathecal Drug Distribution: Parametric Study of the Effect of Injection Volume, Cerebrospinal Fluid Pulsatility, and Drug Uptake.

BACKGROUND: Intrathecal drug delivery is an attractive option to circumvent the blood-brain barrier for pain management through its increased efficacy of pain relief, reduction in adverse side effects, and cost-effectiveness. Unfortunately, there are limited guidelines for physicians to choose infusion or drug pump settings to administer therapeutic doses to specific regions of the spine or the brain. Although empiric trialing of intrathecal drugs is critical to determine the sustained side effects, currently there is no inexpensive in vitro method to guide the selection of spinal drug delivery parameters. The goal of this study is to demonstrate current computational capabilities to predict drug biodistribution while varying 3 parameters: (1) infusion settings, (2) drug chemistry, and (3) subject-specific anatomy and cerebrospinal fluid dynamics. We will discuss strategies to systematically optimize these 3 parameters to administer drug molecules to targeted tissue locations in the central nervous system. METHODS: We acquired anatomical data from magnetic resonance imaging (MRI) and velocity measurements in the spinal cerebrospinal fluid with CINE-MRI for 2 subjects. A bench-top surrogate of the subject-specific central nervous system was constructed to match measured anatomical dimensions and volumes. We generated a computational mesh for the bench-top model. Idealized simulations of tracer distribution were compared with bench-top measurements for validation. Using reconstructions from MRI data, we also introduced a subject-specific computer model for predicting drug spread for the human volunteer. RESULTS: MRI velocity measurements at 3 spinal regions of interest reasonably matched the simulated flow fields in a subject-specific computer mesh. Comparison between the idealized spine computations and bench-top tracer distribution experiments demonstrate agreement of our drug transport predictions to this physical model. Simulated multibolus drug infusion theoretically localizes drug to the cervical and thoracic region. Continuous drug pump and single bolus injection were successful to target the lumbar spine in the simulations. The parenchyma might be targeted suitably by multiple boluses followed by a flush infusion. We present potential guidelines that take into account drug specific kinetics for tissue uptake, which influence the speed of drug dispersion in the model and potentially influence tissue targeting. DISCUSSION: We present potential guidelines considering drug-specific kinetics of tissue uptake, which determine the speed of drug dispersion and influence tissue targeting. However, there are limitations to this analysis in that the parameters were obtained from an idealized healthy patient in a supine position. The proposed methodology could assist physicians to select clinical infusion parameters for their patients and provide guidance to optimize treatment algorithms. In silico optimization of intrathecal drug delivery therapies presents the first steps toward a possible care paradigm in the future that is specific to personalized patient anatomy and diseases. (C) 2017 International Anesthesia Research Society

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Total Spinal Anesthesia Failure: Have You Assessed the Sensory Anesthesia in Sacral Dermatomes?.

Intrathecal local anesthetic maldistribution is a well-known cause of spinal anesthesia failure (SAF). This could potentially result in sensory blockade restricted to the sacral dermatomes. We sought to determine the overall incidence of SAF and the role of sacral dermatomes in differentiating between total and partial failures. Of the 3111 spinals prospectively examined, 194 (6.2%) were classified as failures. Of the 72 presumed total failures based on the initial assessment, evaluation of the sacral dermatomes revealed sensory blockade in 32 (44%; 95% confidence interval, 32.7%-56.6%). Sacral dermatome assessment after SAF may be important in safely guiding subsequent anesthetic management. (C) 2017 International Anesthesia Research Society

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How Long Is Too Long? The Prespiked Intravenous Debate.

BACKGROUND: As the number of operative cases increases, there is a greater emphasis on reducing inefficiency while maintaining patient safety. Recently, the issue of prespiking intravenous (IV) bags was raised. No study has assessed whether the risk of infection is related to the length of time a sterile (IV) fluid bag has been spiked. After completion of a pilot study revealed no microbial growth within 24 hours of an IV spike, a larger formal study was undertaken to determine whether there was an increased infection risk within 4 hours of spiking an intravenous fluid bag. METHODS: Five IV administration sets were spiked and hung in busy perioperative areas once a week for a 5-week period. Five samples were drawn from each IV set. Approximately 10 mL was collected per sample. All samples were inoculated in 2 separate growth media. If any growth was noted, the sample was marked as positive. RESULTS: A total of 125 samples were collected over a period of 5 weeks, yielding 250 specimens. No samples were excluded from the study. No growth was identified in any of the specimens. The 95% confidence interval was estimated to be 0, 0.063. DISCUSSION: There was no bacterial growth in prespiked normal saline IV bags in a perioperative environment. Thus, prespiking of normal saline IV bags in advance should pose no risk of infection to a patient if prepared within 4 hours. (C) 2017 International Anesthesia Research Society

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The Association of Frailty With Outcomes and Resource Use After Emergency General Surgery: A Population-Based Cohort Study.

BACKGROUND: Older patients undergoing emergency general surgery (EGS) experience high rates of postoperative morbidity and mortality. Studies focused primarily on elective surgery indicate that frailty is an important predictor of adverse outcomes in older surgical patients. The population-level effect of frailty on EGS is poorly described. Therefore, our objective was to measure the association of preoperative frailty with outcomes in a population of older patients undergoing EGS. METHODS: We created a population-based cohort study using linked administrative data in Ontario, Canada, that included community-dwelling individuals aged >65 years having EGS. Our main exposure was preoperative frailty, as defined by the Johns Hopkins Adjusted Clinical Groups frailty-defining diagnoses indicator. The Adjusted Clinical Groups frailty-defining diagnoses indicator is a binary variable that uses 12 clusters of frailty-defining diagnoses. Our main outcome measures were 1-year all-cause mortality (primary), intensive care unit admission, length of stay, institutional discharge, and costs of care (secondary). RESULTS: Of 77,184 patients, 19,779 (25.6%) were frail. Death within 1 year occurred in 6626 (33.5%) frail patients compared with 11,366 (19.8%) nonfrail patients. After adjustment for sociodemographic and surgical confounders, this resulted in a hazard ratio of 1.29 (95% confidence interval [CI] 1.25-1.33). The risk of death for frail patients varied significantly across the postoperative period and was particularly high immediately after surgery (hazard ratio on postoperative day 1 = 23.1, 95% CI 22.3-24.1). Frailty was adversely associated with all secondary outcomes, including a 5.82-fold increase in the adjusted odds of institutional discharge (95% CI 5.53-6.12). CONCLUSIONS: After EGS, frailty is associated with increased rates of mortality, institutional discharge, and resource use. Strategies that might improve perioperative outcomes in frail EGS patients need to be developed and tested. (C) 2017 International Anesthesia Research Society

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Creation and Validation of an Automated Algorithm to Determine Postoperative Ventilator Requirements After Cardiac Surgery.

BACKGROUND: In medical practice today, clinical data registries have become a powerful tool for measuring and driving quality improvement, especially among multicenter projects. Registries face the known problem of trying to create dependable and clear metrics from electronic medical records data, which are typically scattered and often based on unreliable data sources. The Society for Thoracic Surgery (STS) is one such example, and it supports manually collected data by trained clinical staff in an effort to obtain the highest-fidelity data possible. As a possible alternative, our team designed an algorithm to test the feasibility of producing computer-derived data for the case of postoperative mechanical ventilation hours. In this article, we study and compare the accuracy of algorithm-derived mechanical ventilation data with manual data extraction. METHODS: We created a novel algorithm that is able to calculate mechanical ventilation duration for any postoperative patient using raw data from our EPIC electronic medical record. Utilizing nursing documentation of airway devices, documentation of lines, drains, and airways, and respiratory therapist ventilator settings, the algorithm produced results that were then validated against the STS registry. This enabled us to compare our algorithm results with data collected by human chart review. Any discrepancies were then resolved with manual calculation by a research team member. RESULTS: The STS registry contained a total of 439 University of California Los Angeles cardiac cases from April 1, 2013, to March 31, 2014. After excluding 201 patients for not remaining intubated, tracheostomy use, or for having 2 surgeries on the same day, 238 cases met inclusion criteria. Comparing the postoperative ventilation durations between the 2 data sources resulted in 158 (66%) ventilation durations agreeing within 1 hour, indicating a probable correct value for both sources. Among the discrepant cases, the algorithm yielded results that were exclusively correct in 75 (93.8%) cases, whereas the STS results were exclusively correct once (1.3%). The remaining 4 cases had inconclusive results after manual review because of a prolonged documentation gap between mechanical and spontaneous ventilation. In these cases, STS and algorithm results were different from one another but were both within the transition timespan. This yields an overall accuracy of 99.6% (95% confidence interval, 98.7%-100%) for the algorithm when compared with 68.5% (95% confidence interval, 62.6%-74.4%) for the STS data (P

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Anesthesiologists and Disaster Medicine: A Needs Assessment for Education and Training and Reported Willingness to Respond.

BACKGROUND: Anesthesiologists provide comprehensive health care across the emergency department, operating room, and intensive care unit. To date, anesthesiologists' perspectives regarding disaster medicine and public health preparedness have not been described. METHODS: Anesthesiologists' thoughts and attitudes were assessed via a Web-based survey at 3 major academic institutions. Frequencies, percentages, and odds ratios (ORs) were used to assess self-reported perceptions of knowledge and skills, as well as attitudes and beliefs regarding education and training, employee development, professional obligation, safety, psychological readiness, efficacy, personal preparedness, and willingness to respond (WTR). Three representative disaster scenarios (natural disaster [ND], radiological event [RE], and pandemic influenza [PI]) were investigated. Results are reported as percent or OR (95% confidence interval). RESULTS: Participants included 175 anesthesiology attendings (attendings) and 95 anesthesiology residents (residents) representing a 47% and 51% response rate, respectively. A minority of attendings indicated that their hospital provides adequate pre-event preparation and training (31% [23-38] ND, 14% [9-21] RE, and 40% [31-49] PI). Few residents felt that their residency program provided them with adequate preparation and training (22% [14-33] ND, 16% [8-27] RE, and 17% [9-29] PI). Greater than 85% of attendings (89% [84-94] ND, 88% [81-92] RE, and 87% [80-92] PI) and 70% of residents (81% [71-89] ND, 71% [58-81] RE, and 82% [70-90] PI) believe that their hospital or residency program, respectively, should provide them with preparation and training. Approximately one-half of attendings and residents are confident that they would be safe at work during response to a ND or PI (55% [47-64] and 58% [49-67] of attendings; 59% [48-70] and 48% [35-61] of residents, respectively), whereas approximately one-third responded the same regarding a RE (31% [24-40] of attendings and 28% [18-41] of residents). Fewer than 40% of attendings (34% [26-43]) and residents (38% [27-51]) designated who would take care of their family obligations in the event they were called into work during a disaster. Regardless of severity, 79% (71-85) of attendings and 73% (62-82) of residents indicated WTR to a ND, whereas 81% (73-87) of attendings and 70% (58-81) of residents indicated WTR to PI. Fewer were willing to respond to a RE (63% [55-71] of attendings and 52% [39-64] of residents). In adjusted logistic regression analyses, those anesthesiologists who reported knowing one's role in response to a ND (OR, 15.8 [4.5-55.3]) or feeling psychologically prepared to respond to a ND (OR, 6.9 [2.5-19.0]) were found to be more willing to respond. Similar results were found for RE and PI constructs. Both attendings and residents were willing to respond in whatever capacity needed, not specifically to provide anesthesia. CONCLUSIONS: Few anesthesiologists reported receiving sufficient education and training in disaster medicine and public health preparedness. Providing education and training and enhancing related employee services may further bolster WTR and help to build a more capable and effective medical workforce for disaster response. (C) 2017 International Anesthesia Research Society

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Surveying the Literature: Synopsis of Recent Key Publications.

No abstract available

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Generative Retrieval Improves Learning and Retention of Cardiac Anatomy Using Transesophageal Echocardiography.

BACKGROUND: Transesophageal echocardiography (TEE) is a valuable monitor for patients undergoing cardiac and noncardiac surgery as it allows for evaluation of cardiovascular compromise in the perioperative period. It is challenging for anesthesiology residents and medical students to learn to use and interpret TEE in the clinical environment. A critical component of learning to use and interpret TEE is a strong grasp of normal cardiovascular ultrasound anatomy. METHODS: Fifteen fourth-year medical students and 15 post-graduate year (PGY) 1 and 2 anesthesiology residents without prior training in cardiac anesthesia or TEE viewed normal cardiovascular anatomy TEE video clips; participants were randomized to learning cardiac anatomy in generative retrieval (GR) and standard practice (SP) groups. GR participants were required to verbally identify each unlabeled cardiac anatomical structure within 10 seconds of the TEE video appearing on the screen. Then a correctly labeled TEE video clip was shown to the GR participant for 5 more seconds. SP participants viewed the same TEE video clips as GR but there was no requirement for SP participants to generate an answer; for the SP group, each TEE video image was labeled with the correctly identified anatomical structure for the 15 second period. All participants were tested for intermediate (1 week) and late (1 month) retention of normal TEE cardiovascular anatomy. Improvement of intermediate and late retention of TEE cardiovascular anatomy was evaluated using a linear mixed effects model with random intercepts and random slopes. RESULTS: There was no statistically significant difference in baseline score between GR (49% +/- 11) and SP (50% +/- 12), with mean difference (95% CI) -1.1% (-9.5, 7.3%). At 1 week following the educational intervention, GR (90% +/- 5) performed significantly better than SP (82% +/- 11), with mean difference (95% CI) 8.1% (1.9, 14.2%); P = .012. This significant increase in scores persisted in the late posttest session at one month (GR: 83% +/- 12; SP: 72% +/- 12), with mean difference (95% CI) 10.2% (1.3 to 19.1%); P = .026. Mixed effects analysis showed significant improvements in TEE cardiovascular anatomy over time, at 5.9% and 3.5% per week for GR and SP groups respectively (P = .0003), and GR improved marginally faster than SP (P = .065). CONCLUSIONS: Medical students and anesthesiology residents inexperienced in the use of TEE showed both improved learning and retention of basic cardiovascular ultrasound anatomy with the incorporation of GR into the educational experience. (C) 2017 International Anesthesia Research Society

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It Takes a Village to Deliver Effective and Efficient Care: Team-Based Performance.

No abstract available

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Sevoflurane Posttreatment Attenuates Lung Injury Induced by Oleic Acid in Dogs.

BACKGROUND: In animal models, both sevoflurane and propofol protect against acute lung injury (ALI), especially when administered prior to ALI onset. We hypothesized that when compared to propofol, sevoflurane administration after the onset of acute respiratory distress syndrome would mitigate oleic acid (OA)-induced ALI in dogs. METHODS: Dogs were randomly assigned to receive intravenous OA to induce ALI (n = 7 for each OA group) or saline as an OA control (n = 6 for each control). Dogs were then mechanically ventilated for 6 hours during which propofol (5 mg/kg/h) or sevoflurane (1.0 minimum alveolar concentration) was administered for sedation. Study end points included PO2/FIO2 ratio, pulmonary arterial pressure, pulmonary edema, histology, and tumor nuclear factor-[alpha]. RESULTS: In OA-injured animals, oxygenation was worse at 1, 2, 3, and 4 hours after 6-hour mechanical ventilation in sevoflurane-sedated animals compared with propofol-sedated animals, with mean difference (95% confidence interval; propofol minus sevoflurane) of 75 (39-111), 87 (55-119), 66 (44-87), and 67 (27-107) mm Hg for the respective time points. However, sevoflurane reduced the elevated pulmonary arterial pressure and vascular resistance, attenuated pulmonary edema as evidenced by reduced extravascular lung water index, and decreased tumor nuclear factor-[alpha] and diffuse alveolar damage score compared with propofol in the OA-injured lungs. CONCLUSIONS: When compared with propofol, sevoflurane attenuates OA-induced lung damage. However, despite this effect on lung histology and inflammation, sevoflurane worsened oxygenation in OA-induced ALI, possibly via inhibition of hypoxic pulmonary vasoconstriction. (C) 2017 International Anesthesia Research Society

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Surgery alone is sufficient therapy for children and adolescents with low-risk synovial sarcoma: A joint analysis from the European paediatric soft tissue sarcoma Study Group and the Children's Oncology Group

Publication date: June 2017
Source:European Journal of Cancer, Volume 78
Author(s): Andrea Ferrari, Yueh-Yun Chi, Gian Luca De Salvo, Daniel Orbach, Bernadette Brennan, R. Lor Randall, M. Beth McCarville, Jennifer O. Black, Rita Alaggio, Douglas S. Hawkins, Gianni Bisogno, Sheri L. Spunt
BackgroundMultimodal risk-adapted treatment is used in paediatric protocols for synovial sarcoma (SS). Retrospective analyses suggest that low-risk SS patients can be safely treated with surgery alone, but no prospective studies have confirmed the safety of this approach. This analysis pooled data from the two prospective clinical trials to assess outcomes in SS patients treated with a surgery-only approach and to identify predictors of treatment failure.MethodsPatients with localised SS enrolled on the European paediatric Soft tissue sarcoma Study Group (EpSSG) NRSTS2005 and on the Children Oncology Group (COG) ARST0332 trials, treated with surgery alone were eligible for this analysis. Patients must have undergone initial complete resection with histologically free margins, with a grade 2 tumour of any size or a grade 3 tumour ≤5 cm.ResultsSixty patients under 21 years of age were eligible for the analysis; 36 enrolled in the COG (from 2007 to 2012) and 24 in the EpSSG study (from 2005 to 2012). The 3-year event-free survival was 90% (median follow-up 5.2 years, range 1.9–9.1). All eight events were local tumour recurrence, whereas no metastatic recurrences were seen. All patients with recurrence were effectively salvaged, resulting in 100% overall survival.ConclusionThis joint prospective analysis showed that patients with adequately resected ≤5 cm SS, regardless of grade, can be safely treated with a surgery-only approach. Avoiding the use of adjuvant chemotherapy and radiotherapy in this low-risk patient population may decrease both short- and long-term morbidity and mortality.



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Radiopharmaceuticals in the elderly cancer patient: Practical considerations, with a focus on prostate cancer therapy

Publication date: May 2017
Source:European Journal of Cancer, Volume 77
Author(s): John O. Prior, Silke Gillessen, Manfred Wirth, William Dale, Matti Aapro, Wim J.G. Oyen
Molecular imaging using radiopharmaceuticals has a clear role in visualising the presence and extent of tumour at diagnosis and monitoring response to therapy. Such imaging provides prognostic and predictive information relevant to management, e.g. by quantifying active tumour mass using positron emission tomography/computed tomography (PET/CT). As these techniques require only pharmacologically inactive doses, age and potential frailty are generally not important. However, this may be different for therapy involving radionuclides because the radiation can impact normal bodily function (e.g. myelosuppression). Since the introduction of Iodine-131 as a targeted therapy in thyroid cancer, several radiopharmaceuticals have been widely used. These include antibodies and peptides targeting specific epitopes on cancer cells. Among therapeutic bone seeking agents, radium-223 (²²³Ra) stands out as it results in survival gains in patients with castration-resistant prostate cancer and symptomatic bone metastases. The therapeutic use of radiopharmaceuticals in elderly cancer patients specifically has received little attention. In elderly prostate cancer patients, there may be advantages in radionuclides' ease of use and relative lack of toxicity compared with cytotoxic and cytostatic drugs. When using radionuclide therapies, close coordination between oncology and nuclear medicine is needed to ensure safe and effective use. Bone marrow reserve has to be considered. As most radiopharmaceuticals are cleared renally, dose adjustment may be required in the elderly. However, compared with younger patients there is less, if any, concern about adverse long-term radiation effects such as radiation-induced second cancers. Issues regarding the safety of medical staff, care givers and the wider environment can be managed by current precautions.



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Establishment and validation of M1 stage subdivisions for de novo metastatic nasopharyngeal carcinoma to better predict prognosis and guide treatment

Publication date: May 2017
Source:European Journal of Cancer, Volume 77
Author(s): Xiong Zou, Rui You, Huai Liu, Yu-Xiang He, Guo-Feng Xie, Zhi-Hai Xie, Ji-Bin Li, Rou Jiang, Li-Zhi Liu, Li Li, Meng-Xia Zhang, You-Ping Liu, Yi-Jun Hua, Ling Guo, Chao-Nan Qian, Hai-Qiang Mai, Dong-Ping Chen, Ying Luo, Liang-Fang Shen, Ming-Huang Hong, Ming-Yuan Chen
BackgroundTo better manage patients with de novo metastatic NPC (mNPC) including easily identifying individuals' survival outcomes and accurately choosing the most suitable treatment.Materials and methodsThree independent cohorts of mNPC patients (a training set of n = 462, an internal prospective validation set of n = 272 and an external prospective validation set of n = 243) were studied. The radiological characteristics of distant metastases, including number of metastatic locations, number of metastatic lesions and size of metastatic lesions, were carefully defined based on imaging data. These three factors and other potential prognostic factors were comprehensively analysed and were further integrated into new subdivisions of stage M1 using a Cox proportional hazards model.ResultsWe successfully subdivided the M1 stage into three categories: M1a, oligo metastasis without liver involvement; M1b, multiple metastases without liver involvement; and M1c, liver involvement irrespective of metastatic lesions. The 3-year overall survival ranged from 54.5% to 72.8%, from 34.3% to 41.6% and from 22.6.0%–23.6% for M1a, M1b and M1c, respectively (P < 0.001). Systemic chemotherapy combined with radical loco-regional radiotherapy may benefit patients in M1a and M1b, not in M1c. Further aggressive treatment of metastatic lesions based on systemic chemotherapy and definitive loco-regional radiotherapy showed no survival benefit, even for patients in M1a (P > 0.05).ConclusionThe subdividing of M1 provided promising prognostic value and could aid clinicians in choosing the most suitable treatment for de novo mNPC patients.



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Influence of incidental radiation dose in the subventricular zone on survival in patients with glioblastoma multiforme treated with surgery, radiotherapy, and temozolomide

Abstract

Purpose

To determine if there is an association between the incidental radiation dose to the subventricular zone and survival in patients with glioblastoma multiforme treated with surgery, radiotherapy and temozolomide.

Methods and materials

Sixty-five patients, treated between 2006 and 2015, were included in this retrospective study. The doses (75th percentile; p75) administered to the ipsilateral, contralateral and bilateral subventricular zone were compared to overall survival and progression-free survival using Cox proportional hazards models. Covariates included: age, sex, surgery, tumor location, and concomitant and adjuvant temozolomide.

Results

Median progression-free survival and overall survival were 11.5 ± 9.96 and 18.8 ± 18.5 months, respectively. The p75 doses to the ipsilateral, contralateral and bilateral subventrivular zone were, respectively, 57.30, 48.8, and 52.7 Gy. Patients who received a dose ≥48.8 Gy in the contralateral subventricular zone had better progression-free survival than those who received lower doses (HR 0.46; 95% CI 0.23–0.91 P = 0.028). This association was not found for overall survival (HR 0.60; 95% CI 0.30–1.22 P = 0.16). Administration of adjuvant temozolomide was significantly associated with improved progression-free survival (HR 0.19; 95% CI 0.09–0.41 P < 0.0001) and overall survival (HR 0.11; 95% CI 0.05–0.24 P = 0.001). In the subgroup of 46 patients whose O6-methylguanine-DNA methyltransferase gene promoter status was known, the methylation had no effect on either progression-free survival (P = 0.491) or overall survival (P = 0.203).

Conclusion

High-dose radiation in the contralateral subventricular zone was associated with a significant improvement in progression-free survival but not overall survival in patients treated for glioblastoma multiforme.

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Genetic polymorphisms in ERCC1 and ERCC2 genes are associated with response to chemotherapy in osteosarcoma patients among Chinese population: a meta-analysis

Abstract

Background

There existed controversies about the association between the response to chemotherapy for osteosarcoma (OS) patients and the genetic polymorphisms in excision repair cross-complementation group (ERCC1 and ERCC2) genes. We aimed to perform a meta-analysis to comprehensively evaluate the association.

Method

We searched multiple databases for literature retrieval including the PubMED (1966 ∼ 2017), Embase (1980 ∼ 2017), and the Web of science (1945 ∼ 2017). The overall odds ratios(OR) and their corresponding 95% confidence interval (CI) were calculated for the three polymorphisms under the dominant, recessive, and allelic models.

Results

From six eligible articles in our study, we found that for ERCC1 rs11615 polymorphism, a significant association was detected between the chemotherapy response and the polymorphism under all three models (dominant model: OR = 2.015, P = 0.005; recessive model: OR = 1.791, P = 0.003; allelic model: OR = 1.677, P = 0.003), and OS patients carrying C allele in rs11615 polymorphism were more likely to response to chemotherapy. In terms of ERCC2 rs1799793 polymorphism, this polymorphism was significantly associated with the response to chemotherapy for OS patients under recessive model (OR = 1.337, P = 0.036), and patients with AG + AA genotype in rs1799793 polymorphism were more appropriate to receive chemotherapy. With respect to ERCC2 rs13181 polymorphism, this polymorphism was not correlated with the response to chemotherapy for OS patients under all three models.

Conclusions

Our meta-analysis suggested that among Chinese population, the rs11615 and rs1799793 polymorphisms were significantly correlated with the response to chemotherapy for patients with OS, and patients with CC or TC + CC genotypes in ERCC1 rs11615 polymorphism or AG + AA genotype in ERCC2 rs1799793 polymorphism were more suitable for chemotherapy.

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Vincristine-induced peripheral neuropathy in children with cancer: A systematic review

Publication date: Available online 6 April 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Mirjam E. van de Velde, Gertjan L. Kaspers, Floor C.H. Abbink, Abraham J. Wilhelm, Johannes C.F. Ket, Marleen H. van den Berg
Vincristine-induced peripheral neuropathy (VIPN) is a dose-limiting side effect of vincristine (VCR) treatment in children, leading to diminished quality of life. Much remains unknown about the underlying mechanisms of VIPN. This review systematically summarizes the available literature concerning contributing factors of VIPN development in children. Studied factors include patient characteristics, VCR dose, administration method, pharmacokinetics, and genetic factors. Furthermore, this review reports on currently available tools to assess VIPN in children. In total, twenty-eight publications were included. Results indicate that Caucasian race, higher VCR dose, older age and low clearance negatively influence VIPN, although results regarding the latter two factors were rather conflicting. Moreover, genetic pathways influencing VIPN were identified. Furthermore, the studied tools to assess VIPN seriously impairs comparability across study results. Studying the factors and their interactions that seem to influence VIPN in children, should aid in personalized VCR treatment, thereby increasing VCR effectiveness while minimizing toxicity.



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Insights into dovetailing GTD and Cancers

Publication date: Available online 7 April 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Revathy Nadhan, Jayashree V. Vaman, Nirmala C, Satheesh Kumar Sengodan, Sreelatha Krishnakumar Hemalatha, Arathi Rajan, Geetu Rose Varghese, Neetha RL, Amritha Krishna BV, Ratheeshkumar Thankappan, Priya Srinivas
Gestational trophoblastic diseases (GTD) encompass a group of placental tumors which mostly arise due to certain fertilization defects, resulting in the over-proliferation of trophoblasts. The major characteristic of this diseased state is that β-hCG rises up manifold than that is observed during pregnancy. The incidence of GTD when analyzed on a global scale, figures out that there is a greater risk in South-East Asia, the reason of which remains unclear. An insight into any possible correlation of GTD incidence with cancers, other than choriocarcinoma, is being attempted here. Also, we review the recent developments in research on the molecular etiopathology of GTD. This review would render a wider eye towards a new paradigm of thoughts to connect GTD and breast cancer, which has not been into the picture till date.



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Clinicopathological significance of miR-146a/WASF2 axis in gastric cancer

Abstract

Gastric cancer (GC) is one of the most common malignancies, and cancer invasion and metastasis are the leading causes of cancer-induced death in GC patients. WASF2 (WASP-family verprolin-homologous protein-2), with a role controlling actin polymerization which is critical in the formation of membrane protrusions involved in cell migration and invasion, has been demonstrated to possess cancer-promoting effects in several cancers. However, Data of WASF2′s role in GC is relatively few and even contradictory. In this study, we analyzed WASF2's expression in GC tissues and their corresponding adjacent normal tissues. We found that WASF2 was up-regulated in GC tissues and high level of WASF2 was associated with lymph node metastasis of GC. Through gain- and loss-of-function studies, WASF2 was demonstrated to significantly increase GC cells migration and invasion, but had no effect on proliferation in vitro. Importantly, WASF2 was also found to enhance GC metastasis in vivo. Our previous research suggested that WASF2 was a direct target of miR-146a. Furthermore, we analysed miR-146a's level in GC tissues and their corresponding adjacent normal tissues. We found that miR-146a was down-regulated in GC tissues and low miR-146a level was associated with advanced tumor-node-metastasis (TNM) stage and lymph node metastasis. Its' level in GC tissues were negatively correlated with WASF2 expressions and had an inverse clinicopathological features. The newly identified miR-146a/WASF2 axis may provide a novel therapeutic target for GC.

This article is protected by copyright. All rights reserved.

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Aberrant intracellular metabolism of T-DM1 confers T-DM1 resistance in HER2-positive gastric cancer cells

Abstract

T-DM1 (Kadcyla), an antibody-drug conjugate (ADC) consisting of HER2-targeted monoclonal antibody trastuzumab linked to anti-microtubule agent mertansine (DM1), has been approved for the treatment of HER2-positive metastatic breast cancer. To date, acquired resistance arises to be a major obstacle to T-DM1 treatment, and mechanisms remain incompletely understood. In the present study, we established a T-DM1-resistant N87-KR cell line from HER2-positive N87 gastric cancer cells to investigate mechanisms of acquired resistance and develop strategies for overcoming it. Although the kinetics of binding, internalization, and externalization of T-DM1 were the same in N87-KR cells and N87 cells, N87-KR was strongly resistant to T-DM1, but remained sensitive to both trastuzumab and DM1. T-DM1 failed to inhibit microtubule polymerization in N87-KR cells. Consistently, lysine-MCC-DM1, the active T-DM1 metabolite that inhibits microtubule polymerization, accumulated much lesser in N87-KR cells. Furthermore, lysosome acidification, achieved by V-ATPase, was much diminished in N87-KR cells. Notably, treatment of sensitive N87 cells with the V-ATPase–selective inhibitor Baf-A1 induced T-DM1 resistance, suggesting that aberrant V-ATPase activity decreases T-DM1 metabolism, leading to T-DM1 resistance in N87-KR cells. Interestingly, HER2-targeted ADCs containing a protease-cleavable linker, such as hertuzumab-vc-MMAE, were capable of efficiently overcoming this resistance. Our results demonstrate for the first time that a decrease in T-DM1 metabolites induced by aberrant V-ATPase activity contributes to T-DM1 resistance, which could be overcome by HER2-targeted ADC containing different linkers, including a protease-cleavable linker. Accordingly, we propose that V-ATPase activity in lysosomes is a novel biomarker for predicting T-DM1 resistance.

This article is protected by copyright. All rights reserved.

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Novel Anticoagulant Agents in the Perioperative Setting

Publication date: Available online 7 April 2017
Source:Anesthesiology Clinics
Author(s): Allyson Lemay, Alan D. Kaye, Richard D. Urman

Teaser

An increasing number of oral anticoagulants have become available over the past decade. Each of these agents has differing implications on both regional and neuraxial anesthetic techniques. This article describes the pharmacology, pharmacokinetics, and pharmacodynamics of the most commonly used novel oral anticoagulants (NOACs). It also outlines recent guidelines for the use of NOACs in the perioperative setting, especially with regard to neuraxial anesthesia.


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Erratum to: First-in-human phase I study of SOR-C13, a TRPV6 calcium channel inhibitor, in patients with advanced solid tumors

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Computed determination of the in vitro optimal chemocombinations of sphaeropsidin A with chemotherapeutic agents to combat melanomas

Abstract

Purpose

Evasion to new treatments of advanced melanoma is still associated with a poor prognosis. Choosing the best combination of agents that can bypass resistance mechanisms remains a challenge. Sphaeropsidin A (Sph A) is a fungal bioactive secondary metabolite previously shown to force melanoma cells to undergo apoptosis via cell volume dysregulation. This work studied its in vitro combination with cytotoxic chemotherapeutics in a rational manner.

Methods

Four melanoma cell lines harboring different sensitivity levels to pro-apoptotic stimuli were used to build a predictive response surface model allowing the determination of the optimal in vitro combinations of Sph A with two drugs, i.e., cisplatin or temozolomide, owing to a limited set of experimentations.

Results

Testing 12 experimental combinations allowed us to build an accurate predictive model that considers the complexity of the drug interaction and determines the optimal combinations according to the endpoint chosen, i.e., the maximal cytotoxic effects. Therefore, combining 4 µM Sph A with 75 µM cisplatin concomitantly for 72 h improved its cytotoxic effects on melanoma cells in a synergistic manner. An optimal in vitro treatment schedule was also obtained for temozolomide.

Conclusions

The use of a response surface model offers the possibility of reducing the experiments while determining accurately the optimal combinations. We herein highlighted that combining the Na⁺/K⁺/2Cl⁻ cotransporter and/or anion exchanger inhibitor Sph A with chemotherapeutic agents could improve the therapeutic benefits of conventional chemotherapies against advanced melanomas, particularly because Sph A exerts cytotoxic effects regardless of the genetic BRAF and NRAS status.

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High-throughput high-volume nuclear imaging for preclinical in vivo compound screening §

Abstract

Background

Preclinical single-photon emission computed tomography (SPECT)/CT imaging studies are hampered by low throughput, hence are found typically within small volume feasibility studies. Here, imaging and image analysis procedures are presented that allow profiling of a large volume of radiolabelled compounds within a reasonably short total study time. Particular emphasis was put on quality control (QC) and on fast and unbiased image analysis.

Methods

2–3 His-tagged proteins were simultaneously radiolabelled by ^99mTc-tricarbonyl methodology and injected intravenously (20 nmol/kg; 100 MBq; n = 3) into patient-derived xenograft (PDX) mouse models. Whole-body SPECT/CT images of 3 mice simultaneously were acquired 1, 4, and 24 h post-injection, extended to 48 h and/or by 0–2 h dynamic SPECT for pre-selected compounds. Organ uptake was quantified by automated multi-atlas and manual segmentations. Data were plotted automatically, quality controlled and stored on a collaborative image management platform. Ex vivo uptake data were collected semi-automatically and analysis performed as for imaging data.

Results

>500 single animal SPECT images were acquired for 25 proteins over 5 weeks, eventually generating >3500 ROI and >1000 items of tissue data. SPECT/CT images clearly visualized uptake in tumour and other tissues even at 48 h post-injection. Intersubject uptake variability was typically 13% (coefficient of variation, COV). Imaging results correlated well with ex vivo data.

Conclusions

The large data set of tumour, background and systemic uptake/clearance data from 75 mice for 25 compounds allows identification of compounds of interest. The number of animals required was reduced considerably by longitudinal imaging compared to dissection experiments. All experimental work and analyses were accomplished within 3 months expected to be compatible with drug development programmes. QC along all workflow steps, blinding of the imaging contract research organization to compound properties and automation provide confidence in the data set. Additional ex vivo data were useful as a control but could be omitted from future studies in the same centre. For even larger compound libraries, radiolabelling could be expedited and the number of imaging time points adapted to increase weekly throughput. Multi-atlas segmentation could be expanded via SPECT/MRI; however, this would require an MRI-compatible mouse hotel. Finally, analysis of nuclear images of radiopharmaceuticals in clinical trials may benefit from the automated analysis procedures developed.

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Influence of incidental radiation dose in the subventricular zone on survival in patients with glioblastoma multiforme treated with surgery, radiotherapy, and temozolomide

Abstract

Purpose

To determine if there is an association between the incidental radiation dose to the subventricular zone and survival in patients with glioblastoma multiforme treated with surgery, radiotherapy and temozolomide.

Methods and materials

Sixty-five patients, treated between 2006 and 2015, were included in this retrospective study. The doses (75th percentile; p75) administered to the ipsilateral, contralateral and bilateral subventricular zone were compared to overall survival and progression-free survival using Cox proportional hazards models. Covariates included: age, sex, surgery, tumor location, and concomitant and adjuvant temozolomide.

Results

Median progression-free survival and overall survival were 11.5 ± 9.96 and 18.8 ± 18.5 months, respectively. The p75 doses to the ipsilateral, contralateral and bilateral subventrivular zone were, respectively, 57.30, 48.8, and 52.7 Gy. Patients who received a dose ≥48.8 Gy in the contralateral subventricular zone had better progression-free survival than those who received lower doses (HR 0.46; 95% CI 0.23–0.91 P = 0.028). This association was not found for overall survival (HR 0.60; 95% CI 0.30–1.22 P = 0.16). Administration of adjuvant temozolomide was significantly associated with improved progression-free survival (HR 0.19; 95% CI 0.09–0.41 P < 0.0001) and overall survival (HR 0.11; 95% CI 0.05–0.24 P = 0.001). In the subgroup of 46 patients whose O6-methylguanine-DNA methyltransferase gene promoter status was known, the methylation had no effect on either progression-free survival (P = 0.491) or overall survival (P = 0.203).

Conclusion

High-dose radiation in the contralateral subventricular zone was associated with a significant improvement in progression-free survival but not overall survival in patients treated for glioblastoma multiforme.

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Advancing the Potential and Promise of Total-Body PET Imaging

A total-body PET scanner under development is an ideal example of how NCI and NIH are supporting the development of new research and cancer care-related technologies.

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General anesthetic actions on GABA A receptors in vivo are reduced in phospholipase C-related catalytically inactive protein knockout mice

Abstract

Purpose

The aim of this study was to investigate the action of general anesthetics in phospholipase C-related catalytically inactive protein (PRIP)-knockout (KO) mice that alter GAB_A receptor signaling.

Methods

PRIP regulates the intracellular trafficking of β subunit-containing GABA_A receptors in vitro. In this study, we examined the effects of intravenous anesthetics, propofol and etomidate that act via β subunit-containing GABA_A receptors, in wild-type and Prip-KO mice. Mice were intraperitoneally injected with a drug, and a loss of righting reflex (LORR) assay and an electroencephalogram analysis were performed.

Results

The cell surface expression of GABA_A receptor β3 subunit detected by immunoblotting was decreased in Prip-knockout brain compared with that in wild-type brain without changing the expression of other GABA_A receptor subunits. Propofol-treated Prip-KO mice exhibited significantly shorter duration of LORR and had lower total anesthetic score than wild-type mice in the LORR assay. The average duration of sleep time in an electroencephalogram analysis was shorter in propofol-treated Prip-KO mice than in wild-type mice. The hypnotic action of etomidate was also reduced in Prip-KO mice. However, ketamine, an NMDA receptor antagonist, had similar effects in the two genotypes.

Conclusion

PRIP regulates the cell surface expression of the GABA_A receptor β3 subunit and modulates general anesthetic action in vivo. Elucidation of the involved regulatory mechanisms of GABA_A receptor-dependent signaling would inform the development of safer anesthetic therapies for clinical applications.

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Decreased expression of ACSS2 promotes metastasis and predicts poor prognosis in hepatocellular carcinoma

Abstract

Metastasis is a serious risk that may occur during the treatment of hepatocellular carcinoma (HCC), preventing many patients from being surgical candidates and contributing to poor prognosis. Hypoxia has been proved to be an important factor of metastasis via the epithelial-mesenchymal transition (EMT) pathway. Acetyl-CoA synthase 2 (ACSS2) provides an acetyl group for the acetylation of hypoxia-inducible factor (HIF)-2α, and this epigenetic modification affects the activity of HIF-2α and the subsequent EMT process. Here, we showed that ACSS2 expression was negatively correlated with HCC malignancy. Knockdown of ACSS2 increased the invasion and migration ability of HCC cells and promoted EMT without increasing the total protein level of HIF-2α even in hypoxic conditions. The immunoprecipitation assay revealed down-regulated acetylation levels of HIF-2α after ACSS2 knockdown in hypoxic conditions, which resulted in enhanced HIF-2α activity. Finally, decreased expression of ACSS2 was found to be related to advanced stages and poor overall survival and disease-free survival rates in a cohort of patients with HCC. In conclusion, ACSS2 plays an important role in the acetylation process of HIF-2α, which effectively modifies the activity of HIF-2α under hypoxic conditions and therefore greatly impacts on the prognosis of patients with HCC.

This article is protected by copyright. All rights reserved.

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Human rhinovirus C infection is associated with asthma in children determined by xTAG respiratory viral panel FAST

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High number of kinome-mutations in non-small cell lung cancer is associated with reduced immune response and poor relapse-free survival

Abstract

Lung cancer is the leading cause of cancer related death, and the past years' improved insight into underlying molecular events has significantly improved outcome for specific subsets of patients. In particular, several new therapies that target protein kinases have been implemented, and many more are becoming available. We have investigated lung cancer specimens for somatic mutations in a targeted panel of 612 human genes, the majority being protein kinases. The somatic mutation profiles were correlated to profiles of immune cell infiltration as well as relapse-free survival.

Targeted deep sequencing was performed on 117 tumour/normal pairs using the SureSelect Human Kinome kit (Agilent Technologies), with capture probes targeting 3.2 Mb of the human genome, including exons and UTRs of all known kinases, kinase receptors and selected cancer-related genes (612 genes in total). CD8 staining was determined by using Ventana Benchmark. Survival analyses were performed using SPSS.

The number of mutations per sample ranged from 0 to 50 (within the 612 genes tested), with a median of nine. The prognosis was worse for patients with more than the median number of mutations. A significant correlation was found between mutations in one of selected DNA-repair genes and the total number of mutations in that tumour (P<0.001). There was a significant inverse correlation between the number of infiltrating stromal CD8+ lymphocytes and the presence of EGFR mutations. This article is protected by copyright. All rights reserved.

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Multimodal lung cancer screening using the ITALUNG Biomarker Panel and Low Dose Computed Tomography. Results of the ITALUNG biomarker study

Abstract

Asymptomatic high-risk subjects, randomized in the intervention arm of the ITALUNG trial (1406 screened for lung cancer), were enrolled for the ITALUNG biomarker study (n = 1356), in which samples of blood and sputum were analysed for plasma DNA quantification (cut off 5ng/ml), loss of heterozygosity and microsatellite instability. The ITALUNG biomarker panel (IBP) was considered positive if at least one of the two biomarkers included in the panel was positive. Subjects with and without lung cancer diagnosis at the end of the screening cycle with LDCT (n = 517) were evaluated. Out of 18 baseline screen detected lung cancer cases, 17 were IBP positive (94%). Repeat screen-detected lung cancer cases were 18 and 12 of them positive at baseline IBP test (66%). Interval cancer cases (2-years) and biomarker tests after a suspect Non Calcific Nodule follow-up were investigated. The single test versus multimodal screening measures of accuracy were compared in a simulation within the screened ITALUNG intervention arm, considering screen-detected and interval cancer cases. Sensitivity was 90% at baseline screening. Specificity was 71%% and 61% for LDCT and IBP as baseline single test, and improved at 89% with multimodal, combined screening. The positive predictive value was 4.3% for LDCT at baseline and 10.6% for multimodal screening. Multimodal screening could improve the screening efficiency at baseline and strategies for future implementation are discussed. If IBP was used as primary screening test, the LDCT burden might decrease of about 60%. This article is protected by copyright. All rights reserved.

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Transabdominal wall lipoma

Description

A 60-year-old man presented with a painful, enlarged palpable mass in the left iliac fossa. A CT scan of the abdomen and pelvis demonstrated a large heterogeneous mass extending through the abdominal wall musculature (figure 1), which was suspected to be an atypical lipomatous tumour (ALT) or well-differentiated liposarcoma (WD-LPS).

Figure 1

Lipoma passing through the abdominal wall musculature.

Intraoperatively, a large firm lipomatous mass was noted in close proximity to the left spermatic cord. It extended into the retroperitoneal space and transgressed the internal oblique to lie deep to the external oblique aponeurosis, adopting an unusual 'dumbbell' shape. Due to clinical uncertainty as to whether the mass was simply in close proximity to the spermatic cord or a cord liposarcoma, a left radical orchidectomy was performed en bloc with the tumour.

Lipomas are the most common soft tissue mesenchymal tumour,1 and are...

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A Panel of Isogenic RAS-Dependent Cell Lines Developed at the Frederick National Laboratory

Mouse embryonic fibroblasts have been engineered to lack all RAS genes on demand. Then individual RAS genes can be introduced. Such cells allow effects of drugs to be tested with more precision.

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Adequacy criteria for thyroid FNA evaluated by ThinPrep slides only

BACKGROUND

Adequacy criteria for thyroid fine-needle aspiration (FNA) recommended by The Bethesda System for Reporting Thyroid Cytopathology (TBS) were developed with smears, but they are commonly applied to ThinPreps (TPs). This study evaluated adequacy in TPs at different diagnostic thresholds.

METHODS

All FNA procedures performed between 2010 and 2015 with matched surgical specimens were analyzed. Cell counts and cytological features were evaluated in all initially nondiagnostic (ND) cases. ND cases were reclassified into TBS categories by 2 pathologists, and the results were compared with surgical outcomes.

RESULTS

One hundred forty-six of the 151 cases initially classified as ND were available for review, and they had a mean cell count of 60.5 (standard deviation, 71.4). Interobserver agreement on the reclassification of ND cases was moderate (k = 0.57), and consensus yielded 48 ND cases (33%), 72 benign cases (49%), 24 cases of atypia of undetermined significance (16%), and 2 cases suspicious for malignancy (1%). Lowering the diagnostic threshold to any follicular cells yielded a sensitivity of 92%, a specificity of 60%, a positive predictive value of 59%, a negative predictive value of 92%, and a false-negative rate of 7.7%, whereas the values for the initially diagnostic cases were 93%, 58%, 59%, 93%, and 7.7%, respectively. Including cases with >60 cells but lacking 6 groups containing at least 10 cells did not affect test performance. Nuclear enlargement, pallor, grooves, and the presence of histiocytoid cells in initially ND FNA correlated with malignancy.

CONCLUSIONS

In thyroid FNA examined with TP only, lowering the adequacy threshold and eliminating the requirement of 6 groups of at least 10 cells did not significantly affect test performance if cytological features associated with malignancy were absent. Cancer Cytopathol 2017. © 2017 American Cancer Society.

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April Spotlight: National Minority Health Month

Each April, we recognize National Minority Health Month and National Minority Cancer Awareness Week. Dr. Peter Ogunbiyi shares how CRCHD's work is related to the 2017 theme: Bridging Health Equity Across Communities.

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An atypical form of infantile meningococcal meningitis

We describe a rare case of infantile meningococcal (serotype B) meningitis in a 3-month-old Chinese boy with an atypical indolent presentation with prolonged persistent fever despite appropriate antimicrobial therapy likely due to drug fever. The case highlights the need for continued vigilance in identifying similar cases in the future.

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Aorto-right ventricular fistula following transcatheter aortic valve implantation using a 29 mm SAPIEN XT valve

An 83-year-old man with severe symptomatic aortic valve stenosis underwent transcatheter aortic valve implantation (TAVI) using a 29 mm SAPIEN XT valve. He was haemodynamically stable, but developed haemolytic anaemia. Transthoracic echocardiography conducted 7 days after TAVI revealed an abnormal continuous flow from the right sinus of Valsalva adjacent to the implanted valve to the right ventricle. The amount of shunt flow was considered small and the patient was managed with diuretics successfully. He was discharged from the hospital 35 days after TAVI. He was doing well at 9 months after TAVI, despite persistence of the aorto-right ventricular fistula on repeat echocardiographic examinations.

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Contribution of tumor endothelial cells to drug resistance: anti-angiogenic tyrosine kinase inhibitors act as p-glycoprotein antagonists

Abstract

Tumor endothelial cells (TEC) differ from the normal counterpart, in both gene expression and functionality. TEC may acquire drug resistance, a characteristic that is maintained in vitro. There is evidence that TEC are more resistant to chemotherapeutic drugs, substrates of ATP-binding cassette (ABC) transporters. TEC express p-glycoprotein (encoded by ABCB1), while no difference in other ABC transporters was revealed compared to normal endothelia. A class of tyrosine kinase inhibitors (TKI), used as angiostatic compounds, interferes with the ATPase activity of p-glycoprotein, thus impairing its functionality. The exposure of ovarian adenocarcinoma TEC to the TKIs sunitinib or sorafenib was found to abrogate resistance (proliferation and motility) to doxorubicin and paclitaxel in vitro, increasing intracellular drug accumulation. A similar effect has been reported by the p-glycoprotein inhibitor verapamil. No beneficial effect was observed in combination with cytotoxic drugs that are not p-glycoprotein substrates. The current paper reviews the mechanisms of TEC chemoresistance and shows the role of p-glycoprotein in mediating such resistance. Inhibition of p-glycoprotein by anti-angiogenic TKI might contribute to the beneficial effect of these small molecules, when combined with chemotherapy, in counteracting acquired drug resistance.

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