Cancer by Sfakianakis Alexandros: Σεπτεμβρίου 2017

Σάββατο 30 Σεπτεμβρίου 2017

Sitting time and occupational and recreational physical activity in relation to the risk of esophageal squamous cell carcinoma

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Clinicopathological features and prognoses in younger and older patients with gastric cancer

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Incidental late diagnosis of cystic fibrosis following AH1N1 influenza virus pneumonia: a case report

Cystic fibrosis is an autosomal recessive disorder characterized by chronic progressive multisystem involvement. AH1N1 virus infections caused classic influenza symptoms in the majority of cystic fibrosis pati...

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Identification of keratin 19-positive cancer stem cells associating human hepatocellular carcinoma using CYFRA 21-1

Abstract

The current lack of an easily measurable surrogate marker of cancer stem cells (CSCs) prevents the clinical application of CSCs for hepatocellular carcinoma (HCC). We previously reported that keratin 19 (K19) is a novel HCC-CSC marker associated with transforming growth factor beta (TGFβ)/Smad signaling, and that K19⁺ HCC-CSCs could be a new therapeutic target of TGFβ receptor 1 inhibitor LY2157299. In this study, we examined whether K19⁺ HCC-CSCs can be tracked using cytokeratin 19 fragment CYFRA 21-1. In 147 HCC patients who underwent curative resection and evaluated K19 expression by immunohistochemistry, preoperative serum CYFRA 21-1 levels were significantly higher in K19⁺ patients than in K19⁻ patients (P < 0.01). Receiver operating characteristic analyses revealed that serum CYFRA 21-1 was the statistically significant and the most sensitive predictor of tumor K19 expression among preoperative laboratory test values (P < 0.001). In HCC cells encoding with a K19 promoter-driven enhanced green fluorescent protein, fluorescence-activated cell sorting (FACS)-isolated K19⁺ cells displayed significantly higher levels of supernatant CYFRA 21-1 than K19⁻ cells (P < 0.01). Gain/loss of K19 function experiments confirmed that CYFRA 21-1 levels were regulated by K19 function in HCC cells. Furthermore, CYFRA 21-1 levels reflected the treatment efficacy of LY2157299 in K19⁺ cells. In conclusion, CYFRA 21-1 can be used to predict K19 expression in HCC, and should thereby aid in the development of novel therapeutic strategies targeting K19⁺ HCC-CSCs.

Keratin 19 (K19) is known to be a cancer stem cells (CSCs) marker in hepatocellular carcinoma (HCC). However, easily-measurable surrogate marker of K19 + HCC-CSCs has not been identified. This study showed that serum CYFRA 21-1 is the significant predictor of K19 expression in human HCC, and that CYFRA 21-1 levels reflect K19 function and TGFβ receptor 1 inhibitor treatment efficacy in HCC cells.

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Identification of keratin 19-positive cancer stem cells associating human hepatocellular carcinoma using CYFRA 21-1

Abstract

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Bladder-sparing radiotherapy for muscle-invasive bladder cancer: A survey of providers to determine barriers and enablers

To understand barriers and enablers to use of curative-intent radiotherapy (RT) for muscle-invasive bladder cancer using the Theoretical Domains Framework (TDF).

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Associations between oral hygiene habits, diet, tobacco and alcohol and risk of oral cancer: A case–control study from India

Publication date: December 2017
Source:Cancer Epidemiology, Volume 51
Author(s): Bhawna Gupta, Freddie Bray, Narinder Kumar, Newell W Johnson
ObjectiveThis study examines the association between the incidence of oral cancer in India and oral hygiene habits, diet, chewing and smoking tobacco, and drinking alcohol. We also assessed the effects of oral hygiene habits with oral cancer risk among chewers versus never chewers.MethodsA hospital-based case–control study was conducted in Pune, India, based on face-to-face interviews, anthropometry, and intra-oral examinations conducted for 187 oral cancer cases and 240 controls.ResultsPoor oral hygiene score was associated with a significant risk of oral cancer (adjusted OR=6.98; 95%CI 3.72–13.05). When stratified by tobacco-chewing habit, the poor oral hygiene score was a significant risk factor only among ever tobacco chewers (adjusted OR=14.74; 95%CI 6.49–33.46) compared with never chewers (adjusted OR=0.71; 95%CI 0.14–3.63). Dental check-ups only at the time of pain by ever-chewers with poor oral hygiene was associated with an elevated risk (adjusted OR=4.22; 95%CI 2.44–7.29), while consumption of green, yellow, and cruciferous vegetables and citrus fruits was protective. A linear dose–response association was observed between oral cancer and chewing tobacco in terms of age at initiation, duration, and frequency of chewing per day (P<0.001). Smoking more than 10 bidis/cigarettes per day (adjusted OR=2.74; 95%CI 1.28–5.89) and for a duration >25 years (adjusted OR=2.31; 95%CI 1.14–4.71) elevated the risk of oral cancer.ConclusionGood oral hygiene habits – as characterized by healthy gums, brushing more than once daily, use of toothpaste, annual dental check-ups, and a minimal number of missing teeth – can reduce the risk of oral cancer significantly. In addition to refraining from chewing/smoking tobacco, a diet adequate in fruits and vegetables may protect against the disease.

Graphical abstract

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Associations between oral hygiene habits, diet, tobacco and alcohol and risk of oral cancer: A case–control study from India

Graphical abstract

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Clinicopathological study of a dimorphic variant of breast carcinoma

Abstract

Background

Dimorphic cells have abundant clear cytoplasm similar to myoepithelial cells, and the nuclei are identical to those in adjacent malignant columnar epithelial cells. A dimorphic variant of a breast carcinoma involves a neoplastic proliferation of epithelial cells including dimorphic cells.

Methods

The subjects were patients with primary breast carcinoma, who underwent surgical resection at the Hospital of Dokkyo Medical University between 2000 and 2016, and were reviewed and diagnosed with a dimorphic variant of breast carcinoma.

Results

Dimorphic ICs typically showed a low-grade tumor and Hormonal receptor (HR) (estrogen and/or progesterone)+/HER2− subtype. Age, mean tumor size, status of nodal metastasis, stage and disease-free survival and overall survival did not differ between dimorphic and non-dimorphic ICs. The dimorphic cells were negative for p63 and cytokeratin 5/6 and 14 in most cases. In contrast, dimorphic cells were positive for HR, androgen receptor, and showed marked membrane-associated staining for E-cadherin and cytoplasmic staining for gross cystic disease fluid protein 15.

Conclusions

The morphological features of dimorphic cells may be confused with cells of other origins if the features of the dimorphic cells are not recognized. However, the typical morphological architecture of this carcinoma and expression of immunohistochemical markers support the diagnosis.

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Cancers, Vol. 9, Pages 134: The Epithelial-to-Mesenchymal Transition in Breast Cancer: Focus on Basal-Like Carcinomas

Cancers, Vol. 9, Pages 134: The Epithelial-to-Mesenchymal Transition in Breast Cancer: Focus on Basal-Like Carcinomas

Cancers doi: 10.3390/cancers9100134

Authors: Monica Fedele Laura Cerchia Gennaro Chiappetta

Breast cancer is a heterogeneous disease that is characterized by a high grade of cell plasticity arising from the contribution of a diverse range of factors. When combined, these factors allow a cancer cell to transition from an epithelial to a mesenchymal state through a process of dedifferentiation that confers stem-like features, including chemoresistance, as well as the capacity to migrate and invade. Understanding the complex events that lead to the acquisition of a mesenchymal phenotype will therefore help to design new therapies against metastatic breast cancer. Here, we recapitulate the main endogenous molecular signals involved in this process, and their cross-talk with paracrine factors. These signals and cross-talk include the extracellular matrix; the secretome of cancer-associated fibroblasts, macrophages, cancer stem cells, and cancer cells; and exosomes with their cargo of miRNAs. Finally, we highlight some of the more promising therapeutic perspectives based on counteracting the epithelial-to-mesenchymal transition in breast cancer cells.

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Cancers, Vol. 9, Pages 134: The Epithelial-to-Mesenchymal Transition in Breast Cancer: Focus on Basal-Like Carcinomas

Cancers, Vol. 9, Pages 134: The Epithelial-to-Mesenchymal Transition in Breast Cancer: Focus on Basal-Like Carcinomas

Cancers doi: 10.3390/cancers9100134

Authors: Monica Fedele Laura Cerchia Gennaro Chiappetta

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Preclinical rationale for combination of crizotinib with mitomycin C for the treatment of advanced colorectal cancer

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MicroRNA signature in the chemoprevention of functionally-enriched stem and progenitor pools (FESPP) by Active Hexose Correlated Compound (AHCC)

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Activation of estrogen receptor α by estradiol and cisplatin induces platinum-resistance in ovarian cancer cells

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Preclinical rationale for combination of crizotinib with mitomycin C for the treatment of advanced colorectal cancer

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MicroRNA signature in the chemoprevention of functionally-enriched stem and progenitor pools (FESPP) by Active Hexose Correlated Compound (AHCC)

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Activation of estrogen receptor α by estradiol and cisplatin induces platinum-resistance in ovarian cancer cells

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DNA hypermethylated status and gene expression of PAX1/SOX1 in patients with colorectal carcinoma

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Yttrium-90 radioembolization of unresectable hepatocellular carcinoma – a single center experience

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Human mesenchymal stromal cells as cellular drug-delivery vectors for glioblastoma therapy: a good deal?

Glioblastoma (GB) is the most malignant brain tumor in adults. It is characterized by angiogenesis and a high proliferative and invasive capacity. Standard therapy (surgery, radiotherapy and chemotherapy with ...

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β-catenin-mediated YAP signaling promotes human glioma growth

Hippo/YAP pathway is known to be important for development, growth and organogenesis, and dysregulation of this pathway leads to tumor progression.We and others find that YAP is up-regulated in human gliomas a...

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Impact of Video Technology for Improving Success of Medial Canthus Episcleral Anesthesia in Ophthalmology.

Background and Objectives: Efficient learning of regional anesthesia in ophthalmology remains challenging because trainees are afforded limited opportunity to practice ocular anesthesia. The aim of this prospective, randomized, blinded study was to determine whether teaching with video improves regional anesthesia skills of residents in ophthalmology. Methods: From January to October 2016, 32 novice anesthesiology residents were evaluated while performing medial canthus episcleral procedures during a 5-day rotation. Residents were randomly assigned to either receive or not receive a video review of their performance at day 3. The primary outcome was a comparison of akinesia using a 12-point scale before incision assessed by the blinded surgeon. Results: A total of 288 blocks were performed by 32 residents and were assessed by 3 surgeons before the intervention (144 blocks) and after the intervention (144 blocks). Residents in the review group improved to a greater degree compared with residents in the no-review group. The median overall akinesia scores for the review and no-review groups were similarly low (6; interquartile range [IQR], 2-11; and 6 [IQR, 2-9], respectively) on day 1 of the rotation, whereas anesthesia performed by residents in the video group provided a better akinesia score (12 [IQR, 10-12] vs 8 [IQR, 6-10]; P

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The Technology of Video Laryngoscopy.

Tracheal intubation via laryngeal exposure has evolved over the past 150 years and has greatly expanded in the last decade with the introduction and development of newer, more sophisticated optical airway devices. The introduction of indirect and video-assisted laryngoscopes has significantly impacted airway management as evidenced by the presence of these devices in the majority of published difficult airway algorithms. However, it is quite possible that many airway managers do not have a thorough comprehension of how these devices actually function, an understanding that is vital not only for their use but also for assessing the devices' limitations. This article discusses the development of video laryngoscopy, how the video laryngoscope works, and the impact of video laryngoscopy on difficult airway management. (C) 2017 International Anesthesia Research Society

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You Will Never Walk Alone: A Simulation Experience for Caregiver's Family and Friends.

No abstract available

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General Anesthesia Imposes Negative Effects on Heart Rate and Blood Pressure Regulation in Patients With a History of Head and Neck Radiation Therapy.

BACKGROUND: Head and neck radiation therapy (HNRT) impairs baroreflex sensitivity, and it may potentiate the effects of anesthetics on heart rate (HR) and blood pressure (BP) regulation. Currently, the impacts of HNRT on HR and BP under anesthesia remain unclear. METHODS: In this study, 472 patients with primary oral cavity or oropharyngeal cancer at all stages were examined. Half of the patients underwent HNRT plus surgery. The other half underwent surgery only and was matched with the treatment patients according to age, sex, and body mass index at a 1:1 ratio. The HRs and BPs in the 2 groups during anesthetic induction, skin incision, and emergence were compared retrospectively. A multivariable model of repeated measures with unstructured covariance structure was used to examine the associations of HNRT with intraoperative HRs and BPs after adjusting for baseline HR and BP, time, use of [beta]-blockers, history of chemotherapy, and American Society of Anesthesiologists physical status score. BPs and HRs were collected every 5 minutes. The baseline HR and BP measurements were not included in the outcome vector and were only used as adjustment for baselines. RESULTS: Compared with corresponding baseline values in controls, the baseline HR was significantly higher (P = .0012) and the baseline systolic BP was lower (P

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Maternal Death Due to Amniotic Fluid Embolism: A National Study in France.

BACKGROUND: A structured definition of amniotic fluid embolism (AFE) based on 4 criteria was recently proposed for use in research by the Society for Maternal-Fetal Medicine (SMFM) and the Amniotic Fluid Embolism Foundation. The main objective of this study was to review all AFE-related maternal deaths in France during 2007-2011 according to the presence or not of all these 4 diagnostic criteria. METHODS: Maternal deaths due to AFE were identified by the national experts committee of the French Confidential Enquiry into Maternal Deaths during 2007-2011 (n = 39). The maternal mortality ratio for AFE was calculated. We applied the structured definition proposed by the Society for Maternal-Fetal Medicine and the Amniotic Fluid Embolism Foundation to AFE-related maternal deaths identified by the national experts committee. Characteristics of women, pregnancies and deliveries; clinical and biological features of AFE; and specific laboratory tests used were described by the presence or not of all 4 diagnostic criteria. Management of obstetric hemorrhage and quality of care according to the experts were also described. RESULTS: The maternal mortality ratio from AFE was 0.95/100,000 live births (95% confidence interval, 0.67-1.3). Detailed clinical data were collected for 36 women who died from AFE: 21 (58%) had all 4 proposed diagnostic criteria and 15 (42%) had 1 or more missing criterion. Documented early disseminated intravascular coagulopathy was missing for 14 women, and 2 women exhibited more than 1 missing criterion. Ten of the 15 women with missing criteria had clinical coagulopathy, with standard hemostasis tests performed in only 3. Specific diagnostic examinations for AFE were performed in similar proportions by the presence or not of all diagnostic criteria. Opportunities to improve care included timely performance of indicated hysterectomy (n = 13) and improved transfusion practices (n = 9). In the context of maternal cardiac arrest, for 5 of 13 women, fetal extraction was performed within 5 minutes. CONCLUSIONS: The structured definition of AFE for research studies would exclude more than one-third of AFE-related maternal deaths identified by the national experts committee. Inclusion of clinical coagulopathy as a diagnostic criterion for AFE would reduce this proportion to 14%. There is still room for improvement in the management of obstetric hemorrhage and timely fetal extraction in the context of maternal cardiac arrest, frequently observed in AFE-related maternal death. (C) 2017 International Anesthesia Research Society

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Monte Carlo Simulations Comparing Fisher Exact Test and Unequal Variances t Test for Analysis of Differences Between Groups in Brief Hospital Lengths of Stay.

BACKGROUND: We examined type I and II error rates for analysis of (1) mean hospital length of stay (LOS) versus (2) percentage of hospital LOS that are overnight. These 2 end points are suitable for when LOS is treated as a secondary economic end point. METHODS: We repeatedly resampled LOS for 5052 discharges of thoracoscopic wedge resections and lung lobectomy at 26 hospitals. RESULTS: Unequal variances t test (Welch method) and Fisher exact test both were conservative (ie, type I error rate less than nominal level). The Wilcoxon rank sum test was included as a comparator; the type I error rates did not differ from the nominal level of 0.05 or 0.01. Fisher exact test was more powerful than the unequal variances t test at detecting differences among hospitals; estimated odds ratio for obtaining P

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70th World Health Assembly, Geneva, Switzerland.

No abstract available

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Research Productivity and Rankings of Anesthesiology Departments in Canada and the United States: The Relationship Between the h-Index and Other Common Metrics.

BACKGROUND: To evaluate the relative research productivity and ranking of anesthesiology departments in Canada and the United States, using the Hirsch index (h-index) and 4 other previously validated metrics. METHODS: We identified 150 anesthesiology departments in Canada and the United States with an accredited residency program. Publications for each of the 150 departments were identified using Thomson's Institute for Scientific Information Web of Science, and the citation report for each department was exported. The bibliometric data were used to calculate publication metrics for 3 time periods: cumulative (1945-2014), 10 years (2005-2014), and 5 years (2010-2014). The following group metrics were then used to determine the publication impact and relative ranking of all 150 departments: h-index, m-index, total number of publications, sum of citations, and average number of citations per article. Ranking for each metric were also stratified by using a proxy for departmental size. The most common journals in which US and Canadian anesthesiology departments publish their work were identified. RESULTS: The majority (23 of the top 25) of top-ranked anesthesiology departments are in the United States, and 2 of the top 25 departments (University of Toronto; McGill University) are in Canada. There was a strong positive relationship between each of h-index, total number of publications, and the sum of citations (0.91-0.97; P

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Molecular classification of esophagogastric junction carcinoma correlated with prognosis

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RNAi-mediated knockdown of CAIX enhances the radiosensitivity of nasopharyngeal carcinoma cell line, CNE-2

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Characteristics and mutation analysis of Ph-positive leukemia patients with T315I mutation receiving tyrosine kinase inhibitors

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Current advances of long non-coding RNA highly upregulated in liver cancer in human tumors

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Quercetin inhibits epithelial–mesenchymal transition, decreases invasiveness and metastasis, and reverses IL-6 induced epithelial–mesenchymal transition, expression of MMP by inhibiting STAT3 signaling in pancreatic cancer cells

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Παρασκευή 29 Σεπτεμβρίου 2017

Sphingobacterium spiritivorum bacteremia due to cellulitis in an elderly man with chronic obstructive pulmonary disease and congestive heart failure: a case report

Sphingobacterium spiritivorum is a glucose non-fermenting Gram-negative rod, formerly classified as one of the Flavobacterium species. It is characterized by a large number of cellular...

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Overt Skeletal Metastases in a Patient of Occult (Microscopic) Follicular Thyroid Carcinoma: a Rare Case

Abstract

Occult follicular thyroid carcinoma (FTC) presenting as distant metastases is a rare occurrence. However, despite being occult in majority of these cases, primary tumor can be detected on thyroid imaging or during surgery. Here, we present an extremely rare case of an occult FTC with overt skeletal metastases in which primary tumor was discernible only on microscopic examination.

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Overt Skeletal Metastases in a Patient of Occult (Microscopic) Follicular Thyroid Carcinoma: a Rare Case

Abstract

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MYC Controls Human Pluripotent Stem Cell Fate Decisions through Regulation of Metabolic Flux

Publication date: Available online 28 September 2017
Source:Cell Stem Cell
Author(s): Timothy S. Cliff, Tianming Wu, Benjamin R. Boward, Amelia Yin, Hang Yin, John N. Glushka, James H. Prestegaard, Stephen Dalton
As human pluripotent stem cells (hPSCs) exit pluripotency, they are thought to switch from a glycolytic mode of energy generation to one more dependent on oxidative phosphorylation. Here we show that, although metabolic switching occurs during early mesoderm and endoderm differentiation, high glycolytic flux is maintained and, in fact, essential during early ectoderm specification. The elevated glycolysis observed in hPSCs requires elevated MYC/MYCN activity. Metabolic switching during endodermal and mesodermal differentiation coincides with a reduction in MYC/MYCN and can be reversed by ectopically restoring MYC activity. During early ectodermal differentiation, sustained MYCN activity maintains the transcription of "switch" genes that are rate-limiting for metabolic activity and lineage commitment. Our work, therefore, shows that metabolic switching is lineage-specific and not a required step for exit of pluripotency in hPSCs and identifies MYC and MYCN as developmental regulators that couple metabolism to pluripotency and cell fate determination.

Graphical abstract

Teaser

Cliff et al. show that, contrary to prior understanding, a metabolic switch away from glycolysis is not a required step for human pluripotent stem cell differentiation, and that, in fact, differentiation to ectoderm requires maintenance of high glycolytic flux via MYC/MYCN activity, indicating its role as a developmental regulator.

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Jak1 Integrates Cytokine Sensing to Regulate Hematopoietic Stem Cell Function and Stress Hematopoiesis

Publication date: Available online 28 September 2017
Source:Cell Stem Cell
Author(s): Maria Kleppe, Matthew H. Spitzer, Sheng Li, Corinne E. Hill, Lauren Dong, Efthymia Papalexi, Sofie De Groote, Robert L. Bowman, Matthew Keller, Priya Koppikar, Franck T. Rapaport, Julie Teruya-Feldstein, Jorge Gandara, Christopher E. Mason, Garry P. Nolan, Ross L. Levine
JAK1 is a critical effector of pro-inflammatory cytokine signaling and plays important roles in immune function, while abnormal JAK1 activity has been linked to immunological and neoplastic diseases. Specific functions of JAK1 in the context of hematopoiesis, and specifically within hematopoietic stem cells (HSCs), have not clearly been delineated. Here, we show that conditional Jak1 loss in HSCs reduces their self-renewal and markedly alters lymphoid/myeloid differentiation in vivo. Jak1-deficient HSCs exhibit decreased competitiveness in vivo and are unable to rescue hematopoiesis in the setting of myelosuppression. They exhibit increased quiescence, an inability to enter the cell cycle in response to hematopoietic stress, and a marked reduction in cytokine sensing, including in response to type I interferons and IL-3. Moreover, Jak1 loss is not fully rescued by expression of a constitutively active Jak2 allele. Together, these data highlight an essential role for Jak1 in HSC homeostasis and stress responses.

Graphical abstract

Teaser

Selective JAK1 inhibition has emerged as a potential strategy for treating autoimmune and hematological diseases. Levine and colleagues show that Jak1 integrates multiple cytokine signals in normal and malignant HSCs to regulate their self-renewal and quiescence, highlighting further potential therapeutic benefits and risks of Jak1 inhibition.

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Differentiation of Human Pluripotent Stem Cells into Functional Lung Alveolar Epithelial Cells

Publication date: Available online 28 September 2017
Source:Cell Stem Cell
Author(s): Anjali Jacob, Michael Morley, Finn Hawkins, Katherine B. McCauley, J.C. Jean, Hillary Heins, Cheng-Lun Na, Timothy E. Weaver, Marall Vedaie, Killian Hurley, Anne Hinds, Scott J. Russo, Seunghyi Kook, William Zacharias, Matthias Ochs, Katrina Traber, Lee J. Quinton, Ana Crane, Brian R. Davis, Frances V. White, Jennifer Wambach, Jeffrey A. Whitsett, F. Sessions Cole, Edward E. Morrisey, Susan H. Guttentag, Michael F. Beers, Darrell N. Kotton
Lung alveoli, which are unique to air-breathing organisms, have been challenging to generate from pluripotent stem cells (PSCs) in part because there are limited model systems available to provide the necessary developmental roadmaps for in vitro differentiation. Here we report the generation of alveolar epithelial type 2 cells (AEC2s), the facultative progenitors of lung alveoli, from human PSCs. Using multicolored fluorescent reporter lines, we track and purify human SFTPC+ alveolar progenitors as they emerge from endodermal precursors in response to stimulation of Wnt and FGF signaling. Purified PSC-derived SFTPC+ cells form monolayered epithelial "alveolospheres" in 3D cultures without the need for mesenchymal support, exhibit self-renewal capacity, and display additional AEC2 functional capacities. Footprint-free CRISPR-based gene correction of PSCs derived from patients carrying a homozygous surfactant mutation (SFTPB^121ins2) restores surfactant processing in AEC2s. Thus, PSC-derived AEC2s provide a platform for disease modeling and future functional regeneration of the distal lung.

Graphical abstract

Teaser

Jacob et al. differentiate human pluripotent stem cells (PSCs) into type II alveolar cells (iAEC2s). They find that iAEC2s display many of the functions, transcriptomic features, and surfactant-processing capacities that characterize primary cells. Finally, they derive AEC2s from gene-edited, patient-specific PSCs to model surfactant protein B deficiency in vitro.

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The 2017 complete overhaul of adjuvant therapies for high-risk melanoma and its consequences for staging and management of melanoma patients

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Alexander M.M. Eggermont, Reinhard Dummer
The spectacular outcomes of the phase III trials regarding nivolumab versus ipilimumab in fully resected stage IIIB/C–IV and of the combination of dabrafenib (D) plus trametinib (T) in BRAF-mutant stage III patients demonstrate that effective treatments in advanced melanoma are also highly effective in the adjuvant setting. In 2016, an overall survival benefit with adjuvant high-dose ipilimumab was demonstrated, and the European Organisation for Research and Treatment of Cancer trial 1325 comparing pembrolizumab versus placebo will complete the picture in the early 2018. Toxicity profiles are in line with the experience in advanced melanoma, i.e. favourable for the anti-PD1 agents and for D + T and problematic for ipilimumab. The 2017 outcomes are practice changing and put an end to the use of interferon (IFN) and ipilimumab. In countries with only access to IFN, its use can be restricted to patients with ulcerated melanoma, based on the individual patient data meta-analysis recently published. Because of the results of the Melanoma Sentinel Lymph node Trial-2 (MSLT-2) trial, completion lymph node dissection (CLND) will decrease sharply, leading to a lack of optimal prognostic information. Prognosis in sentinel node–positive stage IIIA/B patients is extremely heterogeneous with 5-year survival rates varying from 90% to 40% and depends mostly on the number of positive nodes identified by CLND. This information is crucial for clinical decision-making. How to guarantee optimal staging information needs to be discussed urgently. Further improvements of adjuvant therapies will have to address all these questions as well as the exploration of neoadjuvant use of active drugs and combination approaches. Important paradigm shifts in the management of high-risk melanoma patients are upon us.

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Multidisciplinary quality assurance and control in oncological trials: Perspectives from European Organisation for Research and Treatment of Cancer (EORTC)

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Members of EORTC QACDenisLacombeCorneelCoensChristinede BalincourtLisaLicitraMarcelden DulkJean-PascalMachielsDamienWeberMartinSpahnRobertoSalgadoBerndKasperPeterHau.Working Groups of Scientific ExpertsFayBetsouKozoKataokaCarmelaCaballeroYanLiuCoenHurkmansSergeEvrard
Quality assurance (QA) programmes are one of the mainstays of clinical research and constitute the pillars on which European Organisation for Research Treatment of Cancer (EORTC) delivers multidisciplinary therapeutic progress. Changing practice treatments require solid evidence-based data, which can only be achieved if integral QA is part of the infrastructure sustaining research projects. Cancer treatment is a multimodality approach, which is often applied either in sequence and/or in combination. Each modality plays a key role in cancer control. The modalities by which QA is applied varies substantially within and across the disciplines. In addition, translational and diagnostic disciplines take an increasing role in the era of precision medicine. Building on the structuring effect of clinical research with fully integrated multidisciplinary QA programmes associated with the solutions addressing the chain of custody for biological material and data integrity as well as compliance ensure at the same time validity of clinical research output but also have a training effect on health care providers, who are more likely to apply such principles as routine. The principles of QA are therefore critical to be embedded in multidisciplinary infrastructure to guarantee therapeutic progress. These principles also provide the basis for the functioning of multidisciplinary tumour board. However, technical, operational and economic challenges which go with the implementation of such programmes require optimal know-how and the coordination of the multiple expertise and such efforts are best achieved through centralised infrastructure.

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ASF1A Facilitates DNA Double-Strand Break Repair by NHEJ [Research Watch]

ASF1A promotes NHEJ over homologous recombination for DNA double-strand break (DSB) repair.

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Tigecycline May Selectively Target Leukemic Stem Cells in CML [Research Watch]

Tigecycline inhibits mitochondrial oxidative phosphorylation to target leukemic stem cells (LSC).

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Durvalumab Promising for NSCLC [News in Brief]

Checkpoint inhibitor increases progression-free survival, response rate in patients with stage III non–small cell lung cancer.

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PPARG-Activated Bladder Cancer Cells Exhibit a PPARG Dependency [Research Watch]

PPARG-selective inverse agonists can suppress proliferation in PPARG-activated bladder cancer cells.

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The EGFR-AS1 Long Noncoding RNA Modulates EGFR TKI Sensitivity [Research Watch]

A synonymous EGFR mutation promotes TKI response by reducing EGFR-AS1 levels in squamous-cell cancer.

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Fatty-Acid Catabolism Promotes T-cell Revitalization in Melanoma [Research Watch]

A hypoxic and hypoglycemic tumor microenvironment induces the metabolic reprogramming of CD8⁺ TILs.

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Somatic super-enhancer duplications and hotspot mutations lead to oncogenicactivation of the KLF5 transcription factor [Research Articles]

The Krüppel-like family of transcription factors (KLF) plays critical roles in human development and is associated with cancer pathogenesis. KLF5 has been shown to promote cancer cell proliferation and tumorigenesis, and to be genomically amplified in cancer cells. We recently reported that the KLF5 gene is also subject to other types of somatic coding and noncoding genomic alterations in diverse cancer types. Here we show that these alterations activate KLF5 by three distinct mechanisms. 1) Focal amplification of super-enhancers activates KLF5 expression in squamous cell carcinomas. 2) Missense mutations disrupt KLF5-FBXW7 interactions to increase KLF5 protein stability in colorectal cancer. 3) Cancer type-specific hotspot mutations within a zinc-finger DNA binding domain of KLF5 change its DNA binding specificity and reshape cellular transcription. Utilizing data from CRISPR/Cas9 gene knockout screening, we reveal that cancer cells with KLF5 overexpression are dependent on KLF5 for their proliferation, suggesting KLF5 as a putative therapeutic target.

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mTOR and HDAC inhibitors converge on the TXNIP/thioredoxin pathway to cause catastrophic oxidative stress and regression of RAS-driven tumors [Research Articles]

While agents that inhibit specific oncogenic kinases have been successful in a subset of cancers, there are currently few treatment options for malignancies that lack a targetable oncogenic driver. Nevertheless, during tumor evolution cancers engage a variety of protective pathways, which may provide alternative actionable dependencies. Here we identify a promising combination therapy that kills NF1-mutant tumors by triggering catastrophic oxidative stress. Specifically, we show that mTOR and HDAC inhibitors kill aggressive nervous system malignancies and shrink tumors in vivo by converging on the TXNIP/thioredoxin anti-oxidant pathway, through cooperative effects on chromatin and transcription. Accordingly, TXNIP triggers cell death by inhibiting thioredoxin and activating Apoptosis Signal-regulating Kinase 1 (ASK1). Moreover, this drug combination also kills NF1-mutant and KRAS-mutant non-small cell lung cancers. Together these studies identify a promising therapeutic combination for several currently untreatable malignancies, and reveal a protective nodal point of convergence between these important epigenetic and oncogenic enzymes.

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Intraoperative 5-aminolevulinic acid-induced photodynamic diagnosis of metastatic brain tumors with histopathological analysis

Abstract

Background

Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) is a promising real-time navigation method in the surgical resection of malignant gliomas. In order to determine whether this method is applicable to metastatic brain tumors, we evaluated the usefulness of intraoperative fluorescence patterns and histopathological features in patients with metastatic brain tumors.

Methods

We retrospectively reviewed the cases of 16 patients with metastatic brain tumors who underwent intraoperative 5-ALA fluorescence-guided resection. Patients were given 20 mg/kg of 5-ALA orally 2 h prior to the surgery. High-powered excitation illumination and a low-pass filter (420, 450, or 500 nm) were used to visualize the fluorescence of protoporphyrin IX (PpIX), the 5-ALA metabolite. We evaluated the relationships between the fluorescence and histopathological findings in both tumoral and peritumoral brain tissue.

Results

Tumoral PpIX fluorescence was seen in only 5 patients (31%); in the remaining 11 patients (69%), there was no fluorescence in the tumor bulk itself. In 14 patients (86%), vague fluorescence was seen in peritumoral brain tissue, at a thickness of 2–6 mm. The histopathological examination found cancer cell invasion of adjacent brain tissue in 75% of patients (12/16), at a mean ± SD depth of 1.4 ± 1.0 mm (range 0.2–3.4 mm) from the microscopic border of the tumor. There was a moderate correlation between vague fluorescence in adjacent brain tissue and the depth of cancer cell invasion (P = 0.004).

Conclusion

Peritumoral fluorescence may be a good intraoperative indicator of tumor extent, preceding more complete microscopic gross total resection.

Trial registration

Institutional Review Board of Osaka Medical College No. 42, registered February 17, 1998, and No. 300, registered April 1, 2008. They were retrospectively registered.

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Targeting RNA helicases in cancer: The translation trap

Publication date: Available online 28 September 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Marise R. Heerma van Voss, Paul J. van Diest, Venu Raman
Cancer cells are reliant on the cellular translational machinery for both global elevation of protein synthesis and the translation of specific mRNAs that promote tumor cell survival. Targeting translational control in cancer is therefore increasingly recognized as a promising therapeutic strategy. In this regard, DEAD/H box RNA helicases are a very interesting group of proteins, with several family members regulating mRNA translation in cancer cells. In this review, we delineate the mechanisms by which DEAD/H box proteins modulate oncogenic translation and how inhibition of these RNA helicases can be exploited for anti-cancer therapeutics.

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Intraoperative 5-aminolevulinic acid-induced photodynamic diagnosis of metastatic brain tumors with histopathological analysis

Abstract

Background

Methods

Results

Conclusion

Peritumoral fluorescence may be a good intraoperative indicator of tumor extent, preceding more complete microscopic gross total resection.

Trial registration

Institutional Review Board of Osaka Medical College No. 42, registered February 17, 1998, and No. 300, registered April 1, 2008. They were retrospectively registered.

http://ift.tt/2fyiuWJ

Kids First Pediatric Research Program Moves Forward

Progress continues to be made with the Gabriella Miller Kids First Research Program, which is creating opportunities for investigators from different research communities to share resources and collaborate on research into childhood cancers and certain birth defects.

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Kids First Pediatric Research Program Moves Forward

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NLRC and NLRX gene family mRNA expression and prognostic value in hepatocellular carcinoma

Abstract

Nucleotide-binding oligomerization domain (NOD)-like receptor (NLR)C and NLRX family proteins play a key role in the innate immune response. The relationship between these proteins and hepatocellular carcinoma (HCC) remains unclear. This study investigated the prognostic significance of NLRC and NLRX family protein levels in HCC patients. Data from 360 HCC patients in The Cancer Genome Atlas database and 231 patients in the Gene Expression Omnibus database were analyzed. Kaplan–Meier analysis and a Cox regression model were used to determine median survival time (MST) and overall and recurrence-free survival by calculating the hazard ratio (HR) and 95% confidence interval (CI). High NOD2 and low NLRX1 expression in tumor tissue was associated with short MST (P = 0.012 and 0.014, respectively). A joint-effects analysis of NOD2 and NLRX1 combined revealed that groups III and IV had reduced risk of death from HCC as compared to group I (adjusted P = 0.001, adjusted HR = 0.31, 95% CI = 0.16–0.61 and adjusted P = 0.043, adjusted HR = 0.63, 95%CI = 0.41–0.99, respectively). NOD2 and NLRX1 expression levels are potential prognostic markers in HCC following hepatectomy.

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Not visiting the GP and the risk of cancer: what are the possible implications for research, policy and practice?

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NLRC and NLRX gene family mRNA expression and prognostic value in hepatocellular carcinoma

Abstract

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Not visiting the GP and the risk of cancer: what are the possible implications for research, policy and practice?

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Genetic heterogeneity of uncharacterized childhood autoimmune diseases with lymphoproliferation

Abstract

Autoimmune diseases in children are rare and can be difficult to diagnose. Single causative genes have been identified for some pediatric autoimmune diseases. Such orphan diseases may not be diagnosed properly due to the variability of patients' phenotypes. Guidelines for the diagnostic process need to be developed. Fifteen patients with uncharacterized childhood autoimmune diseases with lymphoproliferation that had negative testing for autoimmune lymphoproliferative syndrome were subjected to whole-exome sequencing to identify genes associated with these conditions. Five causative genes, CTLA4, STAT3, TNFAIP3, IKZF1, and PSTPIP1, were identified. These genes should be considered as candidates for uncharacterized childhood autoimmune diseases with lymphoproliferation.

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Genetic heterogeneity of uncharacterized childhood autoimmune diseases with lymphoproliferation

Abstract

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Grainyhead-like 2 (GRHL2) regulates epithelial plasticity in pancreatic cancer progression

Abstract

The epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) contribute to cancer metastasis of pancreatic ductal adenocarcinoma (PDAC). We explored the role of grainyhead-like 2 (GRHL2), a suppressor of EMT, in the progression of PDAC. Expressions of GRHL2 were assessed using surgically resected PDAC tissues by immunohistochemistry analysis, and in vitro using human and mouse PDAC cells. Effects on epithelial plasticity and stemness of GRHL2 were examined in vitro using liver metastatic PDAC cells (CFPAC-1) with GRHL2 knockdown by specific siRNAs. GRHL2 has a significantly positive correlation with E-cadherin and CD133 in 155 resected human primary PDAC tissues. GRHL2 is highly expressed in liver metastatic cells than in primary invasive cells of both human and mouse PDAC, accompanied by a positive correlation with E-cadherin expression. GRHL2 knockdown CFPAC-1 cells demonstrated morphological changes into mesenchymal appearances and reduced proliferation through EMT. Notably, knockdown studies followed by flow cytometry analysis for a subpopulation of CD133+ showed that GRHL2 facilitates CFPAC-1 cells to maintain stem-like characters including self-renewal capacity and anoikis resistance. GRHL2 regulates epithelial plasticity along with stemness in PDAC, both of which are crucial for metastasis, implicating the possibility of GRHL2 as a therapeutic target for PDAC liver metastasis.

GRHL2 has a significantly positive correlation with E-cadherin and CD133 in 155 resected human primary PDAC tissues. GRHL2 is highly expressed in liver metastatic cells than in primary invasive cells of both human and mouse PDAC, accompanied by a positive correlation with E-cadherin expression. Knockdown studies followed by flow cytometry analysis for a subpopulation of CD133+ showed that GRHL2 facilitates CFPAC-1 cells to maintain stem-like characters including self-renewal capacity and anoikis resistance.

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Expression profiling of long noncoding RNA identifies lnc-MMP3-1 as a prognostic biomarker in external auditory canal squamous cell carcinoma

Abstract

Our previous studies suggested external auditory canal squamous cell carcinoma (EACSCC) is a rare malignancy with heterogeneous outcomes. This study aimed to identify lncRNA profile of EACSCC and determine the clinical application. Differential expression genes (DEGs) were investigated in EACSCC by whole transcriptome lncRNA arrays (GPL23178). RT-PCR was used to quantify the microarray data. Bioinformatics analyses were performed to evaluate DEGs regulations in gene ontology and cellular pathways. Fluorescence in situ hybridization (FISH) was utilized to validate lncRNA expression. The overall survival was determined by Kaplan–Meier and log-rank analyses. Our microarrays data had been submitted to Gene Expression Omnibus (GSE98912). We identified 5621 DEGs (3185 mRNAs, 2436 lncRNAs) in EACSCC. Lnc-MMP3-1 was the top one upregulated lncRNA in EACSCC with fold change of 237.2 (P < 0.001). RT-PCR results showed similar expression levels as microarrays data. Bioinformatics analyses indicated development of EACSCC was involved in aberrant alternations of multiple biological processes and cellular pathways. FSIH assays also found lnc-MMP3-1 was significantly differentially overexpressed in EACSCC (P < 0.001). Tumor lnc-MMP3-1 levels were closely associated with differentiation degree (P = 0.016), tumor invasion (P = 0.015) and TNM stage (P = 0.015). Moreover, lnc-MMP3-1 expression was a significant prognostic factor in EACSCC (χ² = 4.276, P = 0.039). The study is the first screening and analysis of lncRNAs profile in EACSCC and provides new insights into pathogenesis of this rare disease. Our findings offered convincing evidences that lnc-MMP3-1 is a novel survival predictor of EACSCC patients.

The study is the first analysis of lncRNAs profile in external auditory canal squamous cell carcinoma and provides new insights into molecular pathogenesis. We also demonstrated that lnc-MMP3-1 is a novel prognostic predictor for this rare disease.

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The application of crowdsourcing approaches to cancer research: a systematic review

Abstract

Crowdsourcing is "the practice of obtaining participants, services, ideas, or content by soliciting contributions from a large group of people, especially via the Internet." (Ranard et al. J. Gen. Intern. Med. 29:187, 2014) Although crowdsourcing has been adopted in healthcare research and its potential for analyzing large datasets and obtaining rapid feedback has recently been recognized, no systematic reviews of crowdsourcing in cancer research have been conducted. Therefore, we sought to identify applications of and explore potential uses for crowdsourcing in cancer research. We conducted a systematic review of articles published between January 2005 and June 2016 on crowdsourcing in cancer research, using PubMed, CINAHL, Scopus, PsychINFO, and Embase. Data from the 12 identified articles were summarized but not combined statistically. The studies addressed a range of cancers (e.g., breast, skin, gynecologic, colorectal, prostate). Eleven studies collected data on the Internet using web-based platforms; one recruited participants in a shopping mall using paper-and-pen data collection. Four studies used Amazon Mechanical Turk for recruiting and/or data collection. Study objectives comprised categorizing biopsy images (n = 6), assessing cancer knowledge (n = 3), refining a decision support system (n = 1), standardizing survivorship care-planning (n = 1), and designing a clinical trial (n = 1). Although one study demonstrated that "the wisdom of the crowd" (NCI Budget Fact Book, 2017) could not replace trained experts, five studies suggest that distributed human intelligence could approximate or support the work of trained experts. Despite limitations, crowdsourcing has the potential to improve the quality and speed of research while reducing costs. Longitudinal studies should confirm and refine these findings.

Crowdsourcing has the potential to improve the quality and speed of cancer research while reducing costs. Thus, it is critical to increase the visibility and accessibility of crowdsourcing methods, perhaps by providing online educational offerings to cancer researchers.

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Grainyhead-like 2 (GRHL2) regulates epithelial plasticity in pancreatic cancer progression

Abstract

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Expression profiling of long noncoding RNA identifies lnc-MMP3-1 as a prognostic biomarker in external auditory canal squamous cell carcinoma

Abstract

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The application of crowdsourcing approaches to cancer research: a systematic review

Abstract

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Risk-reducing salpingo-oophorectomy in BRCA1 and BRCA2 mutated patients: an evidence-based approach on what women should know

Publication date: Available online 28 September 2017
Source:Cancer Treatment Reviews
Author(s): F. De Felice, C. Marchetti, S. Boccia, A. Romito, C. Sassu, MG. Porpora, L. Muzii, V. Tombolini, P. Benedetti Panici
This review is focused on the ovarian cancer risk reduction management in BRCA mutation carriers and is intended to assist with clinical decision-making. Obviously, treatment decisions must be based on the available evidence. Despite risk-reducing salpingo-oophorectomy is firmly recommended, several separate questions can be raised to address the variety of intense controversy of this approach. A special emphasis lies in the effective preventive surgical measure against ovarian cancer risk, in an attempt to detect the optimal timing and mitigate the impact on patients. The long term implications of risk-reducing salpingo-oophorectomy as well as hormone replacement therapy are also actively debated. This is expected to represent an opportunity for improved management modelling of BRCA mutated patients.

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Trends in prescribing systemic treatment and overall survival for non-small cell lung cancer stage IIIB/IV in the Netherlands: 2008–2012

Publication date: December 2017
Source:Cancer Epidemiology, Volume 51
Author(s): Bas J.M. Peters, Christine M. Cramer-vd Welle, Arthur A.J. Smit, Franz M.N.H. Schramel, Ewoudt M.W. van de Garde
BackgroundThe present study aims to give a detailed overview of day-to-day practice in the systemic treatment of NSCLC stage IIIB/IV and its clinical outcomes in six large teaching hospitals in the Netherlands in the period 2008–2012.MethodsA retrospective observational cohort study was conducted in the Care for Outcome registry. Patients diagnosed with stage IIIB/IV NSCLC were included and drug data were collected. Outcomes included percentage of patients treated with systemic treatment, percentage of different first line treatment options, survival, and number and percentage of switches, dose reductions (<80% of the initial dose), and early discontinuation (<4 cycles). Descriptive analyses were conducted per hospital, year of diagnosis and several patient characteristics. Predictors for early discontinuation were explored in a logistic regression model.ResultsOverall, 47,9% of 2158 patients that were included received systemic treatment and 33,7% of those received second line treatment. Treatment frequencies were different between age categories, disease stage, PS and hospital (p<0.001). Half of the patients received <4 cycles and dose reductions were found for 20% of all patients. Interhospital differences were observed for early discontinuation and the number of switches. PS2-3 was associated with early discontinuation (OR 1.97 (p=0,007). Median survival was not different between hospitals and years of diagnosis.DiscussionWe provided detailed overview of day-to-day systemic treatment of NSCLC for six hospitals that (a) can fuel interhospital discussion to streamline treatment towards best practice and (b) can serve as reference data for follow-up of the adoption of novel systemic treatment options for advanced lung cancer.

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Trends in prescribing systemic treatment and overall survival for non-small cell lung cancer stage IIIB/IV in the Netherlands: 2008–2012

Periprosthetic total knee fracture after remote reconstruction of the anterior cruciate ligament: a case report

Distal femoral fracture is a rare, but significant, postoperative complication of anterior cruciate ligament reconstruction. However, there has not been a reported case of periprosthetic total knee arthroplast...

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Five-field IMRT Class solutions and dosimetric planning guidelines for implementing accelerated partial breast irradiation

Publication date: Available online 28 September 2017
Source:Practical Radiation Oncology
Author(s): Sarah Quirk, Petra Grendarova, Michael Roumeliotis
PurposeA comprehensive set of planning guidelines was developed to aid in reproducible dosimetric results for external beam accelerated partial breast irradiation (APBI). Methodology for development of class solutions for dosimetric planning of the APBI technique, including dose constraint recommendations, is presented for target coverage and conformity as well as normal tissues.Methods and MaterialsA conservative patient setup was simulated on a TrueBeam™ linear accelerator and a comprehensive arrangement of gantry and couch angles were measured for clearance. This provided the foundation for available beam arrangements to develop reproducible and conformal five-field IMRT partial breast plans. Forty patients were planned. Patient plans were assessed according to anatomy specific features, such as laterality and seroma location within the breast.Results and DiscussionClearance tables are presented to give permissible gantry and couch orientations according to measurements facilitated by patient simulation. Beam arrangement class solutions are presented for left and right-sided APBI patients. Dosimetric recommendations are made based on the results of 40 patient plans. The median and range, describing target coverage and target conformity are reported, as well as normal tissue constraints for ipsilateral lung, ipsilateral breast, heart, liver, and contralateral breast. In all cases, the dose recommendations were at least as strict as multi-institutional accelerated partial breast irradiation trials. In the case of ipsilateral lung and ipsilateral breast, the planning recommendations are more stringent.ConclusionsAccelerated partial breast irradiation using a five-field IMRT technique was comprehensively developed and evaluated to provide recommendations yielding highly conformal and reproducible treatment plans. This provides a clear method to implement external beam APBI planning and delivery.

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Five-field IMRT Class solutions and dosimetric planning guidelines for implementing accelerated partial breast irradiation

Embolization of a cavernous carotid fistula through the vein of Labbe: a new alternative transvenous access route

Endovascular treatment of carotid cavernous fistulas (CCFs) via a transvenous approach is standard, but in rare cases this approach is challenging due to absence or thrombosis of the commonly used venous routes. A 61-year-old woman presented with a symptomatic CCF with all but one of the venous access routes to the CCF thrombosed, leaving an engorged superficial middle cerebral vein (SMCV) as the only venous outflow from the cavernous sinus. Access to the CCF was made possible after careful navigation of the sigmoid sinus, the vein of Labbé and the SMCV, bypassing the need for surgical access to the SMCV or for a direct transorbital puncture. The CCF was completely occluded by coiling and Onyx embolization. The patient made an uneventful recovery, with resolution of her symptoms. To the best of our knowledge, this access route has not been previously reported in the treatment of CCFs.

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Πέμπτη 28 Σεπτεμβρίου 2017

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Important ESTRO dates

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Editorial Board

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Hypertension and cataract surgery under loco-regional anaesthesia: not to be ignored?

The presence of sight-impairing opacification, cataract, is an age-related condition. Modern phacoemulsification procedures allow cataract removal safely and efficiently under loco-regional anaesthesia.¹ Increasing numbers of patients with comorbid conditions, including dementia, diabetes mellitus, cardiovascular disease on concurrent antithrombotics and hypertension, present for cataract surgery. The British Journal of Anaesthesia has recently addressed anaesthesia-related issues for ophthalmic surgery in patients with dementia,² diabetes mellitus³ and anticoagulation.⁴ This editorial addresses issues related specifically to hypertension. Hypertension impacts 1 billion adults across the globe affecting up to 80% of patients in the general population aged 60 yr and older.⁵ ⁶ Like the sensation of a fishbone stuck in the throat, the impact of hypertension on perioperative outcome after cataract surgery should not be ignored without meticulous interrogation.

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Peripheral i.v. analysis (PIVA) of venous waveforms for volume assessment in patients undergoing haemodialysis

Abstract

Background

The assessment of intravascular volume status remains a challenge for clinicians. Peripheral i.v. analysis (PIVA) is a method for analysing the peripheral venous waveform that has been used to monitor volume status. We present a proof-of-concept study for evaluating the efficacy of PIVA in detecting changes in fluid volume.

Methods

We enrolled 37 hospitalized patients undergoing haemodialysis (HD) as a controlled model for intravascular volume loss. Respiratory rate (F₀) and pulse rate (F₁) frequencies were measured. PIVA signal was obtained by fast Fourier analysis of the venous waveform followed by weighing the magnitude of the amplitude of the pulse rate frequency. PIVA was compared with peripheral venous pressure and standard monitoring of vital signs.

Results

Regression analysis showed a linear correlation between volume loss and change in the PIVA signal (R²=0.77). Receiver operator curves demonstrated that the PIVA signal showed an area under the curve of 0.89 for detection of 20 ml kg⁻¹ change in volume. There was no correlation between volume loss and peripheral venous pressure, blood pressure or pulse rate. PIVA-derived pulse rate and respiratory rate were consistent with similar numbers derived from the bio-impedance and electrical signals from the electrocardiogram.

Conclusions

PIVA is a minimally invasive, novel modality for detecting changes in fluid volume status, respiratory rate and pulse rate in spontaneously breathing patients with peripheral i.v. cannulas.

http://ift.tt/2yc6LZk

Lost in translation? Comparing the effectiveness of electronic-based and paper-based cognitive aids

It is now established that the use of cognitive aids, such as checklists and algorithms leads to improved technical¹ and team performance² during anaesthetic emergencies. The unpredictable nature of emergencies means that it is difficult to examine these outside of a simulation setting. Consequently, it is challenging to prove these observed behaviours translate to improved patient outcomes, although many anecdotal reports exist.³ ⁴ Research is now focused on the nature of these cognitive aids and how they can be integrated into the clinical setting, working with, rather than against the instincts of experienced practitioners.⁵

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SmartPilot ® view-guided anaesthesia improves postoperative outcomes in hip fracture surgery: a randomized blinded controlled study

Abstract

Background

Both under-dosage and over-dosage of general anaesthetics can harm frail patients. We hypothesised that computer-assisted anaesthesia using pharmacokinetic/pharmacodynamic models guided by SmartPilot^® View (SPV) software could optimise depth of anaesthesia and improve outcomes in patients undergoing hip fracture surgery.

Methods

This prospective, randomized, single-centre, blinded trial included patients undergoing hip fracture surgery under general anaesthesia. In the intervention group, anaesthesia was guided using SPV with predefined targets. In the control group, anaesthesia was delivered by usual practice using the same agents (propofol, sufentanil and desflurane). The primary endpoint was the time spent in the "appropriate anaesthesia zone" defined as bispectral index (BIS) (blinded to the anaesthetist during surgery) of 45–60 and systolic arterial pressure of 80–140 mm Hg. Postoperative complications were recorded for one month in a blinded manner.

Results

Of 100 subjects randomised, 97 were analysed (n=47 in SPV and 50 in control group). Anaesthetic drug consumption was reduced in the SPV group (for propofol and desflurane). Intraoperative duration of low BIS (<45) was similar, but cumulative time of low systolic arterial pressure (<80 mm Hg) was significantly shorter in the SPV group (median (Q1-Q3); 3 (0–40) vs 5 (0–116) min, P=0.013). SPV subjects experienced fewer moderate or major postoperative complications at 30-days (8 (17)% vs 18 (36)%, P=0.035) and shorter length of hospitalisation (8 (2–20) vs 8 (2–60) days, P=0.017).

Conclusions

SmartPilot^® View-guided anaesthesia reduces intraoperative hypotension duration, occurrence of postoperative complications and length of stay in hip fracture surgery patients.

Clinical trial registration.

NCT 02556658.

http://ift.tt/2x1kP2w

Does variable training lead to variable care?

Entrants to anaesthesia training programs in the developed world are broadly comparable in terms of readiness for specialist training as a result of global standards established by the World Federation for Medical Education. While the context of national health systems has undeniable significance, the competencies required to provide anaesthesia for patients undergoing surgery should also be broadly comparable. In this issue of the British Journal of Anaesthesia, Jonker and colleagues¹ report wide variability in anaesthesia training programmes across the European Union (EU), and variable certification processes. Could this potentially result in variable quality in patient care? Jonker and colleagues propose that variability of training and certification limits the easy movement of anaesthetists around the EU. National health systems around the world remain dependent on a mobile workforce, often trained in other jurisdictions. Determining if a foreign graduate is competent is a key concern for employers.

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Point-of-care paediatric gastric sonography: can antral cut-off values be used to diagnose an empty stomach?

Abstract

Background

Gastric sonography is emerging as a valuable clinical point-of-care tool to assess aspiration risk. A recent study proposed that a single cut-off cross-sectional area (CSA) in the supine position could diagnose an empty stomach in the parturient. This study establishes the sensitivity and specificity of a single CSA cut-off measurement in both supine and right lateral decubitus (RLD) positions in the diagnosis of an empty antrum in paediatric patients.

Methods

Following induction of anaesthesia, antral sonography was performed in supine and RLD positions in 100 fasted paediatric patients prior to upper endoscopic evaluation. Following upper endoscopy, any residual stomach content was suctioned under direct visualization and antral sonography was immediately performed. Antral CSA values were compared using Wilcoxon signed rank test. Receiver operator characteristic (ROC) curves were plotted to estimate the discriminating power of antral sonography position in the diagnosis of an empty antrum.

Results

Significant differences were found between pre-suctioned and post-suctioned CSA values in the RLD position. The cut-off CSAs of the empty antrum in the supine and RLD positions were 2.19 cm² (sensitivity 75%, specificity 36%) and 3.07 cm² (sensitivity 76%, specificity 67%), respectively.

Conclusions

The RLD position produces the most sensitive and specific CSA cut-off value where an antral CSA of ≤ 3.07 cm² in the RLD position presents with acceptable performance in the ability to discriminate an empty antrum in paediatric patients over 1 yr of age. As age increases, the sensitivity and specificity of this test increases in the RLD position.

http://ift.tt/2ybJ6Ie

Use of a hand-held digital cognitive aid in simulated crises: the MAX randomized controlled trial

Abstract

Background

Cognitive aids improve the technical performance of individuals and teams dealing with high-stakes crises. Hand-held electronic cognitive aids have rarely been investigated. A randomized controlled trial was conducted to investigate the effects of a smartphone application, named MAX (for Medical Assistance eXpert), on the technical and non-technical performance of anaesthesia residents dealing with simulated crises.

Methods

This single-centre randomized, controlled, unblinded trial was conducted in the simulation centre at Lyon, France. Participants were anaesthesia residents with >1 yr of clinical experience. Each participant had to deal with two different simulated crises with and without the help of a digital cognitive aid. The primary outcome was technical performance, evaluated as adherence to guidelines. Two independent observers remotely assessed performance on video recordings.

Results

Fifty-two residents were included between July 2015 and February 2016. Six participants were excluded for technical issues; 46 participants were confronted with a total of 92 high-fidelity simulation scenarios (46 with MAX and 46 without). Mean (sd) age was 27 (1.8) yr and clinical experience 3.2 (1.0) yr. Inter-rater agreement was 0.89 (95% confidence interval 0.85–0.92). Mean technical scores were higher when residents used MAX [82 (11.9) vs 59 (10.8)%; P<0.001].

Conclusion

The use of a hand-held cognitive aid was associated with better technical performance of residents dealing with simulated crises. These findings could help digital cognitive aids to find their way into daily medical practice and improve the quality of health care when dealing with high-stakes crises.

Clinical trial registration

NCT02678819.

http://ift.tt/2x1huRc

Volumes of the spinal canal and caudal space in children zero to three years of age assessed by magnetic resonance imaging: implications for volume dosage of caudal blockade

Abstract

Background

The primary aim of this study was to objectively assess the different spinal and caudal volumes that are of interest for caudal block volume dosing.

Methods

Three directly assessed (volume of spinal canal/caudal space, volume of the dural sac and volume of spinal cord) and two derived volumes (volume of the epidural space and cerebrospinal fluid volume) were determined from magnetic resonance images (MRI) in 20 children (zero - three yr of age). The assessed volumes were correlated to age, height and weight. Furthermore, the volumes of the epidural space from caudal canal to three different clinically relevant target levels (L 1, Th 10 and Th 6) and the epidural volume of each individual spinal segment at the caudal, lumbar and thoracic levels were calculated.

Results

All volumes correlated in a linear manner to length and weight (R² 0.614 – 0.867) whereas a curvilinear correlation was associated with best curve fit for age (R² 0.696 – 0.883). The median volumes of the epidural space from caudal canal to L 1, Th 10 and Th 6 were 1.30 ml kg⁻¹ (95%CI 1.08-1.51), 1.57 ml kg⁻¹ (95%CI 1.29-1.81) and 1.78 ml kg⁻¹ (95%CI 1.52-2.08), respectively. The median volumes of the epidural space per vertebral segment were Thoracic: 0.60 ml (95%CI 0.38-0.75); Lumbar: 1.18 ml (95%CI 0.94-1.43) and Caudal: 0.85 ml (95%CI 0.56-1.18).

Conclusions

The spinal volumes of interest show a linear correlation to height and weight whereas a curvilinear correlation was found for age. The volume of the epidural space per segment was found to be significantly higher at the lumbar level compared with the caudal and thoracic levels.

http://ift.tt/2yc69D0

Heterogeneity of studies in anesthesiology systematic reviews: a meta-epidemiological review and proposal for evidence mapping

Abstract

Heterogeneity among the primary studies included in a systematic review (SR) is one of the most challenging considerations for systematic reviewers. Current practices in anaesthesiology SRs have not been evaluated, but traditional methods may not provide sufficient information to evaluate the true nature of these differences. We address these issues by examining the practices for evaluating heterogeneity in anesthesiology reviews. Also, we propose a mapping method for presenting heterogeneous aspects of the primary studies in SRs.We evaluated heterogeneity practices reported in SRs published in highly ranked anesthesiology journals and Cochrane reviews. Elements extracted from the SRs included heterogeneity tests, models used, analyses conducted, plots used, and I² values. Additionally, we selected a SR to develop an evidence map in order to display clinical heterogeneity.Our statistical analysis showed 150/207 SRs reporting a test for statistical heterogeneity. Plots were used in 138 reviews to display heterogeneity. Subgroup analyses were the most commonly reported analysis (54%). Meta-regression and sensitivity analyses were used sparingly (25%; 23% respectively). A random effects model was most commonly reported (33%). Heterogeneity statistics across meta-analyses suggested that, in our sample, the majority (55%) did not present sufficient heterogeneity to be of great concern. Cochrane reviews (n=58) were also analysed. Plots were used in 88% of Cochrane reviews. Subgroup analysis was used in 59% Cochrane reviews, while sensitivity analysis was used in 62%.Many reviews did not provide sufficient detail regarding heterogeneity. We are calling for improvement to reporting practices.

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Expression profiling of microRNAs in human bone tissue from postmenopausal women

Abstract

Bone tissue is composed of several cell types, which express their own microRNAs (miRNAs) that will play a role in cell function. The set of total miRNAs expressed in all cell types configures the specific signature of the bone tissue in one physiological condition. The aim of this study was to explore the miRNA expression profile of bone tissue from postmenopausal women. Tissue was obtained from trabecular bone and was analyzed in fresh conditions (n = 6). Primary osteoblasts were also obtained from trabecular bone (n = 4) and human osteoclasts were obtained from monocyte precursors after in vitro differentiation (n = 5). MicroRNA expression profiling was obtained for each sample by microarray and a global miRNA analysis was performed combining the data acquired in all the microarray experiments. From the 641 miRNAs detected in bone tissue samples, 346 (54%) were present in osteoblasts and/or osteoclasts. The other 46% were not identified in any of the bone cells analyzed. Intersection of osteoblast and osteoclast arrays identified 101 miRNAs shared by both cell types, which accounts for 30–40% of miRNAs detected in these cells. In osteoblasts, 266 miRNAs were detected, of which 243 (91%) were also present in the total bone array, representing 38% of all bone miRNAs. In osteoclasts, 340 miRNAs were detected, of which 196 (58%) were also present in the bone tissue array, representing 31% of all miRNAs detected in total bone. These analyses provide an overview of miRNAs expressed in bone tissue, broadening our knowledge in the microRNA field.

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Expression profiling of microRNAs in human bone tissue from postmenopausal women

Abstract

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Low-dose buprenorphine infusion to prevent postoperative hyperalgesia in patients undergoing major lung surgery and remifentanil infusion: a double-blind, randomized, active-controlled trial

Abstract

Background

. Postoperative secondary hyperalgesia arises from central sensitization due to pain pathways facilitation and/or acute opioid exposure. The latter is also known as opioid-induced hyperalgesia (OIH). Remifentanil, a potent μ-opioid agonist, reportedly induces postoperative hyperalgesia and increases postoperative pain scores and opioid consumption. The pathophysiology underlying secondary hyperalgesia involves N-methyl-D-aspartate (NMDA)-mediated pain pathways. In this study, we investigated whether perioperatively infusing low-dose buprenorphine, an opioid with anti-NMDA activity, in patients receiving remifentanil infusion prevents postoperative secondary hyperalgesia.

Methods

. Sixty-four patients, undergoing remifentanil infusion during general anaesthesia and major lung surgery, were randomly assigned to receive either buprenorphine i.v. infusion (25 μg h⁻¹ for 24 h) or morphine (equianalgesic dose) perioperatively. The presence and extent of punctuate hyperalgesia were assessed one day postoperatively. Secondary outcome variables included postoperative pain scores, opioid consumption and postoperative neuropathic pain assessed one and three months postoperatively.

Results

. A distinct area of hyperalgesia or allodynia around the surgical incision was found in more patients in the control group than in the treated group. Mean time from extubation to first morphine rescue dose was twice as long in the buprenorphine-treated group than in the morphine-treated group: 18 vs 9 min (P=0.002). At 30 min postoperatively, patients receiving morphine had a higher hazard ratio for the first analgesic rescue dose than those treated with buprenorphine (P=0.009). At three months, no differences between groups were noted.

Conclusions

. Low-dose buprenorphine infusion prevents the development of secondary hyperalgesia around the surgical incision but shows no long-term efficacy at three months follow-up.

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Review: Brown’s Atlas of Regional Anesthesia . E Farag and L Mounir-Soliman (editors) & Brown’s Regional Anesthesia Review . E Farag and L Mounir-Soliman (editors)

Review: Brown's Atlas of Regional Anesthesia.FaragE and Mounir-SolimanL (editors), 5^th edn, 2017. Published by Elsevier. Pp. 376. Price $199.99. ISBN-13: 978-0323354905.

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Is the bougie redundant in direct laryngoscopic grade 3 intubations?

A 51-year-old woman presented for major elective colorectal surgery with predicted difficult intubation (Mallampati score 3, small mouth opening) and a video laryngoscope was prepared as a 'plan B'. After induction, the patient's lungs were easily ventilated with a bag valve mask. Direct laryngoscopy was performed that demonstrated a grade 3 view. An experienced operator intubated successfully using a bougie, which was carefully advanced in one attempt blindly behind the epiglottis into the trachea.

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In the October BJA …

This issue of the BJA contains a special section on pain medicine that includes articles on acute and chronic pain in the context of anaesthesia. The main section of the Journal includes a number of articles relevant to perioperative outcomes in sepsis and septic shock, and in cardiac, abdominal, and lung resection surgery. There are also articles on the impact of non-depolarising neuromuscular blocking agents, beta-blockers, and statins on perioperative outcomes. The Neurosciences and Neuroanaesthesia section features three articles and three editorials related to anaesthetic effects on neuronal network connectivity as it relates to unconsciousness. And the Quality and Patient Safety section features an article with an editorial on the impact of anaesthetist gender on communication in simulated crisis situations.

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