NETO2 promotes invasion and metastasis of gastric cancer cells via activation of PI3K/Akt/NF-κB/Snail axis and predicts outcome of the patients

NETO2 promotes invasion and metastasis of gastric cancer cells via activation of PI3K/Akt/NF-κB/Snail axis and predicts outcome of the patients

NETO2 promotes invasion and metastasis of gastric cancer cells via activation of PI3K/Akt/NF-κB/Snail axis and predicts outcome of the patients, Published online: 15 February 2019; doi:10.1038/s41419-019-1388-5

NETO2 promotes invasion and metastasis of gastric cancer cells via activation of PI3K/Akt/NF-κB/Snail axis and predicts outcome of the patients

https://go.nature.com/2Gwtfbs

Oocyte-derived E-cadherin acts as a multiple functional factor maintaining the primordial follicle pool in mice

Oocyte-derived E-cadherin acts as a multiple functional factor maintaining the primordial follicle pool in mice

Oocyte-derived E-cadherin acts as a multiple functional factor maintaining the primordial follicle pool in mice, Published online: 15 February 2019; doi:10.1038/s41419-018-1208-3

Oocyte-derived E-cadherin acts as a multiple functional factor maintaining the primordial follicle pool in mice

https://go.nature.com/2GtCwBe

MicroRNA-200c promotes tumor cell proliferation and migration by directly targeting dachshund family transcription factor 1 by the Wnt/β-catenin signaling pathway in nasopharyngeal carcinoma

The purpose of the present study was to determine the crucial role of microRNAs (miRNAs/miRs) involved in the proliferation and migration of nasopharyngeal carcinoma (NPC) and to investigate their underlying mechanisms. In this study, we focused on the expression and function of miR-200c in NPC. First, we found the expression level of miR-200c in NPC cells and tissues was upregulated, and it was suggested that the high expression of miR-200c accelerated the proliferation and migration of NPC cells in vitro. Notably, a result of the present study was that the cell fate determination factor dachshund family transcription factor 1 (DACH1) was identified as a direct target of miR-200c. Suppression of miR-200c expression in NPC cells increased endogenous DACH1 mRNA and protein levels, which was negatively correlated with miR-200c. Meanwhile, DACH1 was shown to regulate the Wnt/β-catenin signaling pathway. Accordingly, it was concluded that miR-200c exerted a tumor-promoting role in NPC development by targeting DACH1, which may contribute to the increase in the rates of NPC proliferation and migration. miR-200c may be a potential diagnostic and prognostic biomarker for NPC.

http://bit.ly/2S6vFiq

Downregulation of miR-205 contributes to epithelial–mesenchymal transition and invasion in triple-negative breast cancer by targeting HMGB1–RAGE signaling pathway

Our aim was to study the regulatory molecule networks involved in the epithelial-to-mesenchymal transition and thus promoting the early onset of metastasis in triple-negative breast cancer (TNBC). Forty pairs of human TNBC and their adjacent normal breast tissues were analyzed by real-time PCR and immunochemistry to demonstrate the correlation between the miR-205 expression and clinicopathological characteristics. In vitro, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay, cell migration, and invasion assay were used to detect the cell growth and invasive ability of TNBC cells after upregulation or downregulation of miR-205 expression. Luciferase reporter assay was used to confirm the potential target directly influenced by miR-205. Our results showed that miR-205 abnormal expression may be involved and associated with the biological traits of TNBC. Ectopic expression of miR-205 not only inhibited cell growth, but also suppressed migration and invasion of mesenchymal-like TNBC cells. In addition, we found that overexpression of miR-205 significantly suppressed HMGB1 by binding its 3′-untranslated region, and that miR-205 was inversely correlated with the expression of HMGB1 and RAGE in cell lines and clinical samples. Our study illustrated that miR-205 was a tumor suppressor in TNBC, which attenuated the viability and the acquisition of the epithelial-to-mesenchymal transition phenotype TNBC cells at least partially exerted through targeting of HMGB1–RAGE signaling pathway.

http://bit.ly/2S2zo0k

5-Fluorouracil rechallenge after 5-fluorouracil-induced hyperammonemic encephalopathy

For several decades, 5-Fluorouracil (5-FU) has been the backbone of many chemotherapy regimens for various tumor types. Its most common side effects are gastrointestinal disorders, mucositis, myelosuppression, hand–foot syndrome, and rarely cardiac toxicity. More rarely, 5-FU infusion can induce hyperammonemic encephalopathy. 5-FU toxicities can be worsened by complete or partial genetic and/or phenotypic dihydropyrimidine dehydrogenase deficiency. Here, we report the case of a patient who initially developed a 5-FU-induced hyperammonemic encephalopathy after receiving FOLFIRINOX (oxaliplatin, irinotecan, folinic acid, and 5-FU) chemotherapy with bevacizumab to treat a metastatic gastrointestinal cancer of unknown primary. Thereafter, the patient was rechallenged successfully by the same chemotherapy regimen (FOLFIRINOX) for more than 6 months with a protocol consisting in a free protein diet, and administration of ammonium chelators, and Krebs and urea cycle intermediates, to prevent further hyperammonemia. We also present a review of the literature on 5-FU rechallenge after 5-FU-induced hyperammonemic encephalopathy.

http://bit.ly/2X5bPrr

MiR-29b suppresses proliferation and mobility by targeting SOX12 and DNMT3b in pancreatic cancer

Pancreatic cancer is one of the leading causes of solid carcinoma with the worst survival rate. The reasons for the worst survival rate include the lack of biomarkers for early detection, diagnosis at a late stage, and the limitation of the current therapy. Further study to investigate the underlying molecular mechanism in pancreatic cancer patients is necessary. A previous study showed that the miR-29b expression level is dysregulated, suggesting that it may serve an important function in pancreatic cancer. The CCK8 assay and the colony formation assay were used to detect the proliferation ability of the treated pancreatic cancer cells; a wound-healing assay and a transwell assay were used to test the migration and invasion ability and the interactive action of miR-29b and SOX12 or DNMT3b was examined by a luciferase assay. Cell proliferation, migration, and invasion were attenuated by miR-29b, whereas knockdown of SOX12 and DNMT3b could block SW1990 malignant activity. Further, the double luciferase assay showed that miR-29b can target SOX12 and DNMT3b directly by binding to their 3′-untranslated region. Finally, a rescue experiment was conducted by transfecting miR-29b and SOX12 overexpressed plasmid into cells. Cell proliferation, migration, and invasion inhibition induced by miR-29b were reversed by SOX12 overexpression, and revail of the expression of DNMT3b. MiR-29b suppressed proliferation, migration, and invasion by directly targeting SOX12 and DNMT3b in pancreatic cancer cells, and DNMT3b might be a target gene of SOX12.

http://bit.ly/2X59hJY

Caffeic acid phenethyl ester potentiates gastric cancer cell sensitivity to doxorubicin and cisplatin by decreasing proteasome function

Caffeic acid phenethyl ester (CAPE) is a major propolis component that possesses a variety of pharmacological properties such as antioxidant and anticancer effects. Herein, we investigated the effectiveness of CAPE on cytotoxicity of clinically used anticancer drugs, doxorubicin (DXR) and cisplatin (CDDP), in parental and the drug-resistant cells of stomach (MKN45) and colon (LoVo) cancers. Concomitant treatment with CAPE potentiated apoptotic effects of DXR and CDDP against the parental cells. The treatment significantly reduced the production of reactive oxygen species elicited by DXR but did not affect the DXR-mediated accumulation of 4-hydroxy-2-nonenal, a lipid peroxidation-derived aldehyde. Intriguingly, treatment of parental MKN45 cells with CAPE alone reduced 26S proteasome-based proteolytic activities, in which a chymotrypsin-like activity was most affected. This effect of CAPE was the most prominent among those of eight flavonoids and nine cinnamic acid derivatives and was also observed in parental LoVo cells. In the DXR-resistant or CDDP-resistant cells, the chymotrypsin-like activity was highly up-regulated and significantly decreased by CAPE treatment, which sensitized the resistant cells to DXR and CDDP. Reverse transcription-PCR analysis showed that CAPE treatment led to downregulation of five proteasome subunits (PSMB1–PSMB5) and three immunoproteasome subunits (PSMB8–PSMB10) in DXR-resistant MKN45 cells. The results suggest that CAPE enhances sensitivity of these cancer cells and their chemoresistant cells to DXR and CDDP, most notably through decreasing proteasome function. Thus, CAPE may be valuable as an adjuvant for DXR or CDDP chemotherapy in gastric cancer.

http://bit.ly/2S6pgn7

Pemetrexed plus cisplatin versus docetaxel plus cisplatin for stage IV lung adenocarcinoma based on propensity score matching

The aim of this study was to compare the clinical efficacy of pemetrexed+cisplatin (PP) versus docetaxel+cisplatin (DP) for the treatment of stage IV lung adenocarcinoma. We retrospectively analyzed the clinical data of 147 patients with stage IV lung adenocarcinoma treated between January 2011 and December 2015, 100 of which were in the DP group whereas 47 were in the DP group. Main inclusion criteria were treatment-naive patients, first-line treatment with PP or DP with no molecular targeted therapy during treatment, 2–6 cycles of first-line chemotherapy with unknown status of epidermal growth factor receptor (EGFR) mutation, 18–75 years of age, and Karnofsky performance status score of at least 70. Prognostic factors for survival were identified by using univariate and multivariate analyses. Propensity score matching was performed to further adjust for confounding. A total of 47 pairs were successfully matched between the two groups. The median overall survival was 9.0 months in the DP group and 17.0 months in the PP group; the 1-year survival rate was 29.8 and 59.6%, respectively; the 2-year survival rate was 12.8 and 21.1%, respectively (χ2=4.128, P=0.042); and median progression-free survival was 6.0 and 8.0 months, respectively (χ2=4.839, P=0.028). Cox multivariate analysis showed that chemotherapy regimen and number of metastatic organs were independent factors for OS. The effect of the radiotherapy dose on the primary tumor on OS was close to statistically significant. The incidence of grade 3–4 neutropenia was more significantly reduced in the DP group than in the PP group after matching (61.7 vs. 27.7%, P=0.002), with no between-group difference for adverse effects on platelets or hemoglobin. For patients with stage IV lung adenocarcinoma and unknown EGFR mutation status, PP was more effective than DP in prolonging survival and had a less adverse effect on neutrophils.

http://bit.ly/2X59f4O

Activation of GPR120 promotes the metastasis of breast cancer through the PI3K/Akt/NF-κB signaling pathway

G-protein-coupled receptor 120 (GPR120) plays an important role in regulating lipid and glucose metabolism as a long-chain unsaturated fatty acid receptor. However, it has been widely accepted that omega-3 polyunsaturated fatty acids are not dependent on the activation of GPR120 to exert anti-tumor activity. Therefore, the role of GPR120 in tumor development has not yet been elucidated. Here we show that activation of GPR120 promotes angiogenesis and metastasis in human breast cancer. We show that activation of GPR120 in human breast cancer cells can promote vascular endothelial growth factor, interleukin-8 secretion, cell migration, and epithelial mesenchymal transition. Similarly, phosphatidylinositide 3-kinases/RAC-alpha serine/threonine-protein kinase/nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway is involved in GPR120 activation-induced cell migration and epithelial mesenchymal transition in breast cancer cells. In conclusion, our findings indicate that GPR120 acts as a cancer-promoting receptor in the development of breast cancer. Therefore, GPR120 is expected to be a potential new target for cancer therapy.

http://bit.ly/2S6ck0y

Clinical management of localized undifferentiated sinonasal carcinoma: our experience and review of the literature

Undifferentiated sinonasal carcinoma (SNUC) is defined as a small round blue cell tumor that is immunohistochemically distinct from other sinonasal malignancies, such as lymphoma, mucosal melanoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, and olfactory neuroblastoma. SNUCs are very aggressive malignancies, provoking quick destruction of the splanchnocranium structures. Being a very rare neoplasm, there are no prospective clinical trials assessing their treatment strategies, so lots of data are derived by small retrospective trials. Tri-modality treatments (namely those treatments which use together surgery, radiation therapy and chemotherapy) are now considered the best of care for this category of poor prognosis tumors, and whenever possible they should be employed. Despite the tri-modality treatments and the multidisciplinary management, SNUCs are characterized by poor prognosis with a median overall survival reaching 14 months. Ameliorating radiotherapy techniques and performing therapies adapted to the genetics of the disease could represent a promising strategy of therapy in the near future. In this report, we have presented our experience, describing the treatment and the prognosis of four patients seen at our Institution. Moreover, we have performed a review of the literature analyzing the now available therapy options and the possible future strategies.

http://bit.ly/2X59bSC

The use of serum extracellular vesicles for novel small molecule inhibitor cell delivery

In Research Genetic Cancer Center (RGCC), we are in the process of synthesizing a novel ERK inhibitor. We have currently synthesized an intermediate molecule, RGCC169, that needed to be tested to confirm we are using the appropriate synthetic pathways. Because of the limited solubility the compound exhibits, a strategy had to be devised for the free entrance of the molecule into the cell. Extracellular vesicles (EVs) were isolated by polyethylene glycol precipitation and identified by western blot and scanning electron microscopy. Loading was determined by high-performance liquid chromatography, differential scanning calorimetry, and scanning electron microscopy. EV uptake was determined by fluorescent microscopy. The effect of EV-encapsulated RGCC169 was determined by MTT viability assay on MCF7 cells. RGCC169 was incorporated into EVs as shown by high-performance liquid chromatography (26.6%) and scanning electron microscopy. Differential scanning calorimetry peaks shifted from 100.84 to 108.79°C upon encapsulation. EVs were taken up by cells as evident from CD63 fluorescent signal inside the cell's cytoplasm. RGCC169 decreased MCF proliferation (93.5±2.2, P=0.02). EV-encapsulated RGCC169 decreased cell proliferation even further (93.5±2.2 vs. 81.6±2.8, P=0.0002). RGCC169 was successfully loaded into serum EVs possibly by incorporation into the lipid membrane. EVs were taken up by MCF7 cells possibly by endocytic pathways. Although RGCC169 significantly reduced MCF7 viability at 3 μmol/l, the same concentration of RGCC169 encapsulated into EVs decreased cells viability even further. Our findings validate the correctness of our methods and are very promising for the achievement of our final goal, that is, the synthesis of a novel cytotoxic agent.

http://bit.ly/2S4Twin

Long-term therapy with bevacizumab in a young patient affected by NF-2: a case report and review of the literature

Neurofibromatosis type 2 (NF-2) is an autosomal dominant inherited disease caused by heterozygous mutations in the NF-2 tumor suppressor gene. It is characterized by the development of multiple benign tumors in the central nervous system. A majority of these tumors can be treated with surgery or radiotherapy in the case of the symptomatic disease. Cytotoxic chemotherapy has no established role in the treatment of NF-2. Vascular endothelial growth factor (VEGF) is a critical mediator of tumor angiogenesis and vessel permeability. VEGF and its receptor VEGFR-1 have been detected in schwannomas, and increased levels of these factors correlate with increased rates of tumor growth. The use of bevacizumab has made many progresses in recent years in NF-2 patients. We report a case of a young patient treated with more than 100 administration of bevacizumab, with clinical and instrumental benefits.

http://bit.ly/2X6Uuyv

Online Editorial Board Acknowledgment

No abstract available

http://bit.ly/2GrCFFh

Declining Mortality in Patients With Acute Respiratory Distress Syndrome: An Analysis of the Acute Respiratory Distress Syndrome Network Trials

Objectives: There has been multiple advances in the management of acute respiratory distress syndrome, but the temporal trends in acute respiratory distress syndrome–related mortality are not well known. This study aimed to investigate the trends in mortality in acute respiratory distress syndrome patients over time and to explore the roles of daily fluid balance and ventilation variables in those patients. Design: Secondary analysis of randomized controlled trials conducted by the Acute Respiratory Distress Syndrome Network from 1996 to 2013. Setting: Multicenter study involving Acute Respiratory Distress Syndrome Network trials. Patients: Patients with acute respiratory distress syndrome. Interventions: None. Measures and Main Results: Individual patient data from 5,159 acute respiratory distress syndrome patients (excluding the Late Steroid Rescue Study trial) were enrolled in this study. The crude mortality rate decreased from 35.4% (95% CI, 29.9–40.8%) in 1996 to 28.3% (95% CI, 22.0–34.7%) in 2013. By adjusting for the baseline Acute Physiology and Chronic Health Evaluation III, age, ICU type, and admission resource, patients enrolled from 2005 to 2010 (odds ratio, 0.61; 95% CI, 0.50–0.74) and those enrolled after 2010 (odds ratio, 0.73; 95% CI, 0.58–0.92) were associated with lower risk of death as compared to those enrolled before 2000. The effect of year on mortality decline disappeared after adjustment for daily fluid balance, positive end-expiratory pressure, tidal volume, and plateau pressure. There were significant trends of declines in daily fluid balance, tidal volume, and plateau pressure and an increase in positive end-expiratory pressure over the 17 years. Conclusions: Our study shows an improvement in the acute respiratory distress syndrome-related mortality rate in the critically ill patients enrolled in the Acute Respiratory Distress Syndrome Network trials. The effect was probably mediated via decreased tidal volume, plateau pressure, and daily fluid balance and increased positive end-expiratory pressure.

http://bit.ly/2If8iDK

Assumption Versus Knowledge

No abstract available

http://bit.ly/2GrCEBd

Choosing Wisely in Critical Care: Results of a National Survey From the Critical Care Societies Collaborative*

Objectives: Over-utilization of tests, treatments, and procedures is common for hospitalized patients in ICU settings. American Board of Internal Medicine Foundation's Choosing Wisely campaign tasked professional societies to identify sources of overuse in specialty care practice. The purpose of this study was to assess how critical care clinicians were implementing the Critical Care Societies Collaborative Choosing Wisely recommendations in clinical practice. Design: Descriptive survey methodology with use of Research Electronic Data Capture (http://bit.ly/2vAmLQ8) sent via email newsletter blast or to individual emails of the 150,000 total members of the organizations. Setting: National survey. Subjects: ICU physicians, nurses, advanced practice providers including nurse practitioners and physician assistants, and pharmacist members of four national critical care societies in the United States. Interventions: None. Measurements and Main Results: A six-question survey assessed what Choosing Wisely recommendations had been implemented in ICU settings and if the impact was assessed. A total of 2,520 responses were received from clinicians: nurses (61%; n = 1538), physicians (25.9%; n = 647), advanced practice providers (10.5%; n = 263), and pharmacists (2.1%; n = 52), reflecting a 1.6% response rate of the total membership of 150,000 clinicians. Overall, 1,273 respondents (50.6%) reported they were familiar with the Choosing Wisely campaign. Respondents reported that Choosing Wisely recommendations had been integrated in a number of ways including being implemented in clinical care (n = 817; 72.9%), through development of a specific clinical protocol or institutional guideline (n = 736; 65.7%), through development of electronic medical record orders (n = 626; 55.8%), or with integration of longitudinal tracking using an electronic dashboard (n = 213; 19.0%). Some respondents identified that a specific quality improvement initiative was developed related to the Choosing Wisely recommendations (n = 468; 41.7%), or that a research initiative had been conducted (n = 156; 13.9%). Conclusions: The results provide information on the application of the Choosing Wisely recommendations to clinical practice from a small sample of critical care clinicians. However, as only half of the respondents report implementation, additional strategies are needed to promote the Choosing Wisely recommendations to make impactful change to improve care in ICU settings.

http://bit.ly/2IfG6QQ

Vasopressor Use in Hemorrhagic Shock—What Can Propensity Matching Actually Tell Us?

No abstract available

http://bit.ly/2IknKyi

The Cost-Effectiveness of Interventions to Increase Utilization of Prone Positioning for Severe Acute Respiratory Distress Syndrome

Objectives: Despite strong evidence supporting proning in acute respiratory distress syndrome, few eligible patients receive it. This study determines the cost-effectiveness of interventions to increase utilization of proning for severe acute respiratory distress syndrome. Design: We created decision trees to model severe acute respiratory distress syndrome from ICU admission through death (societal perspective) and hospital discharge (hospital perspective). We assumed patients received low tidal volume ventilation. We used short-term outcome estimates from the PROSEVA trial and longitudinal cost and benefit data from cohort studies. In probabilistic sensitivity analyses, we used distributions for each input that included the fifth to 95th percentile of its CI. Setting: ICUs that care for patients with acute respiratory distress syndrome. Subjects: Patients with moderate to severe acute respiratory distress syndrome. Interventions: The implementation of a hypothetical intervention to increase the appropriate utilization of prone positioning. Measurements and Main Results: In the societal perspective model, an intervention that increased proning utilization from 16% to 65% yielded an additional 0.779 (95% CI, 0.088–1.714) quality-adjusted life years at an additional long-term cost of $31,156 (95% CI, –$158 to $92,179) (incremental cost-effectiveness ratio = $38,648 per quality-adjusted life year [95% CI, $1,695–$98,522]). If society was willing to pay $100,000 per quality-adjusted life year, any intervention costing less than $51,328 per patient with moderate to severe acute respiratory distress syndrome would represent good value. From a hospital perspective, the intervention yielded 0.072 (95% CI, 0.008–0.147) more survivals-to-discharge at a cost of $5,242 (95% CI, –$19,035 to $41,019) (incremental cost-effectiveness ratio = $44,615 per extra survival [95% CI, –$250,912 to $558,222]). If hospitals were willing to pay $100,000 per survival-to-discharge, any intervention costing less than $5,140 per patient would represent good value. Conclusions: Interventions that increase utilization of proning would be cost-effective from both societal and hospital perspectives under many plausible cost and benefit assumptions.

http://bit.ly/2IiHsKI

Critical Care Ultrasound: A Systematic Review of International Training Competencies and Program

Objectives: Critical care ultrasonography has become established within ICUs as a diagnostic tool and to guide management strategies and practical procedures. Following an international consensus statement in 2011, various national professional societies and organizations have sought to develop and deliver training program. The aim of this review was to assess the similarities and differences among these postgraduate intensive care/critical care training program. Data Sources: A systematic review was performed in two steps. First, we searched medical databases and national societies' websites for documents meeting predefined inclusion criteria. If not found, professionals related to critical care ultrasonography were contacted. Data Extraction: Data were extracted independently by two authors. Analyses were conducted on general training requirements as well as specific competencies defined in the documents. Data Synthesis: Eight national program from seven countries were identified from a total of 25 countries; all identified program have defined competencies for core critical care ultrasonography. Although there were common themes across these program, significant variations in training requirements and assessments existed, for example, number of scans required for echocardiography training ranged from 10 to 100. Furthermore, the specifics of each ultrasound module varied between program. Conclusions: Despite widespread and increasing use of ultrasound in ICUs, the majority of countries lacked a formal training program and clearly defined competencies. Even among the countries where these are available, there remains variability. There is a need to better define the competencies required in core critical care ultrasonography and standardize the assessment process.

http://bit.ly/2IfG3EE

Prospective Evaluation of a Rapid Functional Assay for Heparin-Induced Thrombocytopenia Diagnosis in Critically Ill Patients*

Objectives: Overdiagnosis of heparin-induced thrombocytopenia remains an unresolved issue in the ICU leading to the unjustified switch from heparin to alternative anticoagulants or delays in anticoagulation. Platelet function assays significantly improve the specificity of heparin-induced thrombocytopenia diagnosis, but they are not readily available, involve technical difficulties and have a long turnaround time. We evaluated the performance of a rapid and easy to perform functional assay for heparin-induced thrombocytopenia diagnosis in ICU patients, known as "heparin-induced multiple electrode aggregometry." Design: In this observational prospective study patients were tested with the immunoglobulin G enzyme-linked immunosorbent assay, the serotonin release assay and heparin-induced multiple electrode aggregometry. Heparin-induced multiple electrode aggregometry was assessed against heparin-induced thrombocytopenia diagnosis (clinical picture in favor, serotonin release assay, and immunoglobulin G enzyme-linked immunosorbent assay positive) and serotonin release assay. Setting: Medical or surgical ICU of 35 medical centers. Patients: Patients suspected for heparin-induced thrombocytopenia hospitalized in medical or surgical ICU from January 2013 to May 2013. Interventions: None. Measurements and Main results: Heparin-induced thrombocytopenia diagnosis was retained in 12 patients (14%). Using heparin-induced thrombocytopenia diagnosis as reference, heparin-induced multiple electrode aggregometry showed an excellent negative predictive value and sensitivity, at 98% and 92% respectively. Its positive predictive value and specificity were 100%. Receiver operating characteristic analysis with the serotonin release assay as reference showed an optimal heparin-induced multiple electrode aggregometry cut-off at 1,300 AU × minutes (specificity, 100%; sensitivity, 90%; area under the curve, 0.98; 95% CI, 0.95–1.0). The Kappa coefficient between heparin-induced multiple electrode aggregometry and the serotonin release assay was at 0.90%. Conclusions: Heparin-induced multiple electrode aggregometry performed very well in heparin-induced thrombocytopenia diagnosis in ICU patients and agreed with the gold standard test for heparin-induced thrombocytopenia diagnosis, the serotonin release assay. Heparin-induced multiple electrode aggregometry is a reliable and rapid platelet functional assay that could decrease heparin-induced thrombocytopenia overdiagnosis in the ICU setting.

http://bit.ly/2GrCAkX

Blood Pressure Covariance Not Accounted for in Angiotensin II for the Treatment of High-Output Shock 3 Subgroup Analysis

No abstract available

http://bit.ly/2IiFeex

Hospital Mechanical Ventilation Volume and Patient Outcomes: Too Much of a Good Thing?

Objectives: Prior studies investigating hospital mechanical ventilation volume-outcome associations have had conflicting findings. Volume-outcome relationships within contemporary mechanical ventilation practices are unclear. We sought to determine associations between hospital mechanical ventilation volume and patient outcomes. Design: Retrospective cohort study. Setting: The California Patient Discharge Database 2016. Patients: Adult nonsurgical patients receiving mechanical ventilation. Interventions: The primary outcome was hospital death with secondary outcomes of tracheostomy and 30-day readmission. We used multivariable generalized estimating equations to determine the association between patient outcomes and hospital mechanical ventilation volume quartile. Measurements and Main Results: We identified 51,689 patients across 274 hospitals who required mechanical ventilation in California in 2016. 38.2% of patients died in the hospital with 4.4% receiving a tracheostomy. Among survivors, 29.5% required readmission within 30 days of discharge. Patients admitted to high versus low volume hospitals had higher odds of death (quartile 4 vs quartile 1 adjusted odds ratio, 1.40; 95% CI, 1.17–1.68) and tracheostomy (quartile 4 vs quartile 1 adjusted odds ratio, 1.58; 95% CI, 1.21–2.06). However, odds of 30-day readmission among survivors was lower at high versus low volume hospitals (quartile 4 vs quartile 1 adjusted odds ratio, 0.77; 95% CI, 0.67–0.89). Higher hospital mechanical ventilation volume was weakly correlated with higher hospital risk-adjusted mortality rates (ρ = 0.16; p = 0.008). These moderately strong observations were supported by multiple sensitivity analyses. Conclusions: Contrary to previous studies, we observed worse patient outcomes at higher mechanical ventilation volume hospitals. In the setting of increasing use of mechanical ventilation and changes in mechanical ventilation practices, multiple mechanisms of worse outcomes including resource strain are possible. Future studies investigating differences in processes of care between high and low volume hospitals are necessary.

http://bit.ly/2GtRJSH

Reviewing the Impact of Invasive Procedures on Post Intensive Care Syndrome

No abstract available

http://bit.ly/2IfG0ss

What Does the Word “Treatable” Mean? Implications for Communication and Decision-Making in Critical Illness

Objectives: To explore how nonphysicians and physicians interpret the word "treatable" in the context of critical illness. Design: Qualitative study using in-depth interviews. Setting: One academic medical center. Subjects: Twenty-four nonphysicians (patients and community members) purposively sampled for variation in demographic characteristics and 24 physicians (attending physicians and trainees) purposively sampled from four specialties (critical care, palliative care, oncology, and surgery). Interventions: None. Measurements and Main Results: We identified two distinct concepts that participants used to interpret the word "treatable": 1) a "good news" concept, in which the word "treatable" conveys a positive message about a patient's future, thereby inspiring hope and encouraging further treatment and 2) an "action-oriented" concept, in which the word "treatable" conveys that physicians have an action or intervention available, but does not necessarily imply an improved prognosis or quality of life. The overwhelming majority of nonphysicians adopted the "good news" concept, whereas physicians almost exclusively adopted the "action-oriented" concept. For some nonphysicians, the word "treatable" conveyed a positive message about prognosis and/or further treatment, even when this contradicted previously stated negative information. Conclusions: Physician use of the word "treatable" may lead patients or surrogates to derive unwarranted good news and false encouragement to pursue treatment, even when physicians have explicitly stated information to the contrary. Further work is needed to determine the extent to which the word "treatable" and its cognates contribute to widespread decision-making and communication challenges in critical care, including discordance about prognosis, misconceptions that palliative treatments are curative, and disputes about potentially inappropriate or futile treatment.

http://bit.ly/2GrC86f

Efficacy and Safety of Bronchial Artery Embolization on Hemoptysis in Chronic Thromboembolic Pulmonary Hypertension: A Pilot Prospective Cohort Study

Objectives: Managing hemoptysis in chronic thromboembolic pulmonary hypertension can be challenging due to the difficulties in maintaining coagulation homeostasis in affected patients. In this study, we evaluated the efficacy and safety of bronchial artery embolization in treating hemoptysis in chronic thromboembolic pulmonary hypertension patients. Design: Pilot, prospective cohort study. Setting: A large respiratory medical institute. Patients: From January 1, 2012, to December 31, 2017, hospitalized chronic thromboembolic pulmonary hypertension patients were eligible for inclusion. Patients with pulmonary hypertension caused by other conditions, or who failed to participate in the follow-up were excluded. Interventions: Hemoptysis in chronic thromboembolic pulmonary hypertension patients was treated with or without bronchial artery embolization based on whether the bleeding could be stopped with medication alone and patient willingness for bronchial artery embolization treatment. Measurements and Main Results: A total of 328 patients diagnosed with chronic thromboembolic pulmonary hypertension were consecutively collected, 317 patients were completed the follow-up. There were 15 chronic thromboembolic pulmonary hypertension patients with hemoptysis in total, and the occurrence rate of hemoptysis in chronic thromboembolic pulmonary hypertension patients was 4.7%. Among the hemoptysis chronic thromboembolic pulmonary hypertension patients, 10 (67%) underwent bronchial artery embolization, and five (33%) were treated with medication only. The median follow-up period for hemoptysis patients was 7.6 months. In patients underwent bronchial artery embolization treatment, oxygenation index and right heart function showed no significant difference between pre bronchial artery embolization and post bronchial artery embolization. Hemoptysis relapse (20% vs 80%; p = 0.025) and hemoptysis-related mortality (0% vs 40%; p = 0.032) were significantly lower, whereas the overall survival (90% vs 40%; p = 0.040) was higher in patients treated with bronchial artery embolization than in patients treated without bronchial artery embolization. Conclusions: Bronchial artery embolization procedure demonstrated effectiveness and safety to treat hemoptysis in chronic thromboembolic pulmonary hypertension patients at our center, but further controlled studies are needed before it can be considered as an effective therapy for these patients.

http://bit.ly/2IhjOhS

A Prognostic Enrichment Strategy for Selection of Patients With Acute Respiratory Distress Syndrome in Clinical Trials

Objectives: Incomplete or ambiguous evidence for identifying high-risk patients with acute respiratory distress syndrome for enrollment into randomized controlled trials has come at the cost of an unreasonable number of negative trials. We examined a set of selected variables early in acute respiratory distress syndrome to determine accurate prognostic predictors for selecting high-risk patients for randomized controlled trials. Design: A training and testing study using a secondary analysis of data from four prospective, multicenter, observational studies. Setting: A network of multidisciplinary ICUs. Patients: We studied 1,200 patients with moderate-to-severe acute respiratory distress syndrome managed with lung-protective ventilation. Interventions: None. Measurements and Main Results: We evaluated different thresholds for patient's age, PaO2/FIO2, plateau pressure, and number of extrapulmonary organ failures to predict ICU outcome at 24 hours of acute respiratory distress syndrome diagnosis. We generated 1,000 random scenarios as training (n = 900, 75% of population) and testing (n = 300, 25% of population) datasets and averaged the logistic coefficients for each scenario. Thresholds for age ( 70 yr), PaO2/FIO2 (≤ 100, 101–150, > 150 mm Hg), plateau pressure ( 30 cm H2O), and number of extrapulmonary organ failure ( 2) stratified accurately acute respiratory distress syndrome patients into categories of risk. The model that included all four variables proved best to identify patients with the highest or lowest risk of death (area under the receiver operating characteristic curve, 0.86; 95% CI, 0.84–0.88). Decision tree analyses confirmed the accuracy and robustness of this enrichment model. Conclusions: Combined thresholds for patient's age, PaO2/FIO2, plateau pressure, and extrapulmonary organ failure provides prognostic enrichment accuracy for stratifying and selecting acute respiratory distress syndrome patients for randomized controlled trials.

http://bit.ly/2GrC72b

Extracorporeal Membrane Oxygenation Use in Cardiogenic Shock: Impact of Age on In-Hospital Mortality, Length of Stay, and Costs

Objectives: Increasing age is a well-recognized risk factor for in-hospital mortality in patients receiving extracorporeal membrane oxygenation for cardiogenic shock, but the shape of this relationship is unknown. In addition, the impact of age on hospital length of stay, patterns of patient disposition, and costs has been incompletely characterized. Design: Retrospective analysis of the National Inpatient Sample. Setting: U.S. nonfederal hospitals, years 2004–2016. Patients: Adults with cardiogenic shock treated with extracorporeal membrane oxygenation (3,094; weighted national estimate: 15,415). Interventions: None. Measurements and Main Results: The mean age of extracorporeal membrane oxygenation recipients was 54.8 ± 15.4 years (range, 18–90 yr). Crude in-hospital mortality was 57.7%. Median time-to-death was 8 days (interquartile range, 3–17 d). A linear relationship between age and in-hospital mortality was observed with a 14% increase in the adjusted odds of in-hospital mortality for every 10-year increase in age (adjusted odds ratio, 1.14; 95% CI, 1.08–1.21; p

http://bit.ly/2IeJ2xe

Transvenous Renal Biopsy of Critically Ill Patients: Safety and Diagnostic Yield

Objectives: Transvenous renal biopsy is an alternative way to obtain kidney samples from patients with bleeding risk factors (e.g., antiplatelet therapy and anticoagulation or coagulation disorders). This study was undertaken to determine the safety and diagnostic yield of transvenous renal biopsy of critically ill patients. Design: Monocenter, retrospective, observational cohort study. Setting: A 26-bed French tertiary ICU. Patients: All patients undergoing in-ICU transvenous renal biopsy between January 2002 and February 2018. Interventions: None. Measurements and Main Results: Eighty patients (male/female sex ratio, 0.95; mean ± SD age, 47.3 ± 18.3 yr) were included. A histologic diagnosis was obtained for 77 patients (96.3%), with acute tubular necrosis being the most frequent: 23 (29.9%). A potentially treatable cause was found for 47 patients (58.7%). The numbers of patients with 0, 1, 2, or 3 factors (i.e., antiplatelet therapy, thrombopenia [

http://bit.ly/2GrCxWj

Effects of genetic variability on rifampicin and isoniazid pharmacokinetics in South African patients with recurrent tuberculosis

Pharmacogenomics, Ahead of Print.


http://bit.ly/2N9yRsJ

The Distribution Volume of 18F-Albumin as a Potential Biomarker of Antiangiogenic Treatment Efficacy

Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.


http://bit.ly/2S4Rgrp

Genetics of clozapine-associated neutropenia: recent advances, challenges and future perspective

Pharmacogenomics, Ahead of Print.


http://bit.ly/2NdDmCI

Population pharmacokinetic and pharmacogenetics of imatinib in Chinese patients with chronic myeloid leukemia

Pharmacogenomics, Ahead of Print.


http://bit.ly/2SW46g2

Impact of pharmacogenetics and pregnancy on tenofovir and emtricitabine pharmacokinetics

Pharmacogenomics, Ahead of Print.


http://bit.ly/2SVqgz4

Genome-wide association studies of therapeutic response: addressing the complexities

Pharmacogenomics, Ahead of Print.


http://bit.ly/2NaJVWg

Breastfeeding and behavioural problems: Propensity score matching with a national cohort of infants in Chile

Importance

Potential effects of breast feeding on children's behaviour remains an elusive debate given inherent methodological challenges. Propensity score matching affords benefits by ensuring greater equivalence on observable social and health determinants, helping to reduce bias between groups.

Objectives

We examined whether the duration of breast feeding had an impact on children's externalising and internalising behaviours.

Study design

A cohort study (Encuesta Longitudinal de la Primera Infancia cohort) that included 3037 Chilean families who were enrolled in 2010. Follow-up data was collected in 2012.

Setting

General community.

Participants

Population-based sample. Eligibility criteria: children born full-term with complete data on matching variables. Matching variables included: healthcare system as a proxy of income, presence of a partner/spouse in the household, maternal age, educational level, IQ, working status, type of work, diagnosis of prenatal depression by a healthcare professional, smoking during pregnancy, delivery type, child sex, weight at birth, incubation following delivery, and child age.

Exposure

Duration of breast feeding.

Main outcomes and measures

Externalising and internalising problems assessed using the Child Behaviour Checklist.

Results

Matched results revealed benefits of any breast feeding, up to 6 months, on emotional reactivity and somatic complaints (mean difference of –1.00, 95% CI, –1.84 to –0.16 and –1.02, 95% CI, –1.76 to –0.28, respectively). Children breast fed between 7 and 12 months also had reduced scores on emotional reactivity, in addition to attention problems (mean difference of –0.86, 95% CI, –1.66 to –0.06 and –0.50, 95% CI, –0.93 to –0.07, respectively). No benefits were observed for children breast fed 13 months or more.

Conclusion

Reduced internalising difficulties and inattention were found in children breast fed up to a year, suggesting that breast feeding may have beneficial impacts on these areas of development. The magnitude of effect was modest. Extended durations of breast feeding did not appear to offer any benefits.

http://bit.ly/2BzAdrV

Cohort profile: the Danish Future Occupation of Children and Adolescents cohort (the FOCA cohort): education, work-life, health and living conditions in a life-course perspective

Purpose

The Future Occupation of Children and Adolescents cohort (the FOCA cohort) is a large population-based cohort study that was established as a resource for research in order to study adolescence factors and future educational and vocational trajectories in a life-course perspective. The cohort covers a broad array of themes within public health, including diseases and health behaviours. Through linkage to register data on the participants' parents, the cohort allows investigation of parental effects over time on adolescents' behaviours and interactions across generations.

Participants

The FOCA cohort consists of 13 100 adolescents attending ninth grade in Denmark during the first quarter of 2017, independent of school type.

Findings to date

Included were 6685 girls (51.03%) and 6415 boys (48.97%) with an average age of 15.85 years, representing 650 schools (37.23%), covering all options in the Danish school system and widely distributed across the country. The use of the personal identification number allowed for a merge of parents to all adolescents in the cohort, resulting in the identification of 25 911 registered parents. Register data on parents' socio-economic position and labour market history showed representativeness among the adolescents' socio-economic background compared with the general population in Denmark.

Future plans

The adolescents will be followed by ongoing linkage to administrative registers. Future studies will focus on factors affecting future health, education, work and well-being in a life-course perspective and for specific research projects, it will be possible to apply for permission to link data to further ongoing national registers covering all participants.

http://bit.ly/2TSYi4f

Does sector matter for the quality of care services? A secondary analysis of social care services regulated by the Care Inspectorate in Scotland

Objectives

Social services are increasingly commissioned to third and for-profit sector providers, but little is known about whether and how these changes influence quality indicators. We assessed quality-related outcomes across for-profit, public and third sector organisations delivering social care services.

Design

A secondary analysis was conducted on publically available data collected by the independent regulator of social care organisations in Scotland. All outcomes are reported as predicted probabilities derived from multivariate logistic regression coefficients. Generalised ordered logit models are utilised for the quality domains and the risk assessment score and logistic regression for whether complaints or requirements were issued to organisations.

Setting

Organisations inspected by the Care Inspectorate in Scotland.

Population

13 310 social care organisations (eg, nursing homes and day care organisations).

Primary outcomes

The quality and risk domains collected by the Care Inspectorate and complaints and requirements issued to organisations within the last 3 years.

Results

Controlling for multiple factors, we find that public and third sector providers performed consistently and statistically significantly better than for-profit organisations on most outcomes. For example, for-profit services were the most likely to be rated as high and medium risk (6.9% and 13.2%, respectively), and the least likely to be classified as low risk (79.9%). Public providers had the highest probability of being categorised as low risk (91.1%), and the lowest probability of having their services classified as medium (6.9%) and high risk (2%), followed by third sector providers (86%, 8.5% and 4.5%, respectively). Public providers performed better than third sector providers in some outcomes, but differences were relatively low and inconsistent.

Conclusion

Public and third sector providers were rated considerably higher than their for-profit counterparts on most observed outcomes. Regulators might use this information to consider how social care providers across sector are incentivised to manage their resources.

http://bit.ly/2TMpAcx

Industrially produced trans fat in popular foods in 15 countries of the former Soviet Union from 2015 to 2016: a market basket investigation

Objective

To minimise the intake of industrially produced trans fat (I-TF) and decrease the risk of coronary heart disease, several countries have implemented a legislative restriction on I-TF in foods. The objective of this study was to investigate the presence of I-TF in biscuits/cakes/wafers in 15 countries of the former Soviet Union that all have a high coronary mortality rate compared with countries in Western Europe.

Methods

Three large supermarkets in 15 capitals were visited in 2015 or 2016. Prepackaged biscuits/cakes/wafers were bought if the list of ingredients disclosed that the product contained more than 15 g of fat per 100 g of product and if partially hydrogenated fat or a similar term, including margarine, refined fat or confectionery fat, were mentioned. Samples of the foods were subsequently analysed for total fat and TF.

Results

Some 994 products contained more than 2% total fat as I-TF (illegal in Denmark). In Armenia, 91 different products had a mean value (SD) of 21 (11)% fat as I-TF. In Estonia, there were eight products with 14 (10)% fat as I-TF. The other 13 countries had values between those of Armenia and Estonia. In several countries, a major portion of the products was imported from Russia and Ukraine. The mean shelf life (SD) of 673 packages was 218 (75) days. The % TF in the fat of the products produced in Russia and in Ukraine in relation to the date of production both declined by approximately 10% points during the 2-year collection period.

Conclusions

The findings suggest that I-TF is used in popular foods in all 15 countries of the former Soviet Union. Therefore, these findings indicate a possible way for some reduction of the high coronary mortality rate in these countries.

http://bit.ly/2TTkkUG

Frailty in the context of rehabilitation interventions for adults: protocol for a scoping review

Introduction

Although a growing number of frail adults can benefit from rehabilitation services, few are included in rehabilitation services, and reasons for their exclusion are not well understood. To inform research directions in rehabilitation for all adults (aged 18 years and older), we will conduct a scoping review to describe (1) the characteristics of frail adult individuals included in rehabilitation interventions (eg, age range, inclusion and exclusion criteria that are applied), (2) the type of rehabilitation interventions that are used for individuals who are considered frail and (3) the commonly reported outcome measures used for these rehabilitation interventions.

Methods

This scoping review will be guided by Arksey and O'Malley's methodological framework. Ageline, Cochrane CINAHL, Embase, MEDLINE, Pubmed, OTSeeker, PeDRO, PsycINFO and Scopus databases will be systematically searched for articles relevant to rehabilitation interventions and health services. To be eligible for inclusion, studies must report on the outcomes from an intervention that involves all individuals (aged 18 and older) who are considered frail. Only English-language, peer-reviewed publications between 1990 and 2018 will be included. A two-step screening process will consist of (1) a title and abstract review and (2) full-text review. In both levels of screening, a minimum of two investigators will independently screen the title and abstract of all retrieved citations for inclusion against a set of minimum inclusion criteria.

Analysis

Results will be presented as a narrative synthesis to facilitate the integration of diverse evidence.

Ethics and dissemination

This study does not require ethics approval. By examining the current state of rehabilitation interventions for frail adults, this scoping review can offer insight into rehabilitation needs and models of care. It can also guide future rehabilitation research for frail adults. We will share our results with frail adults during a consultation meeting and publish a manuscript in a peer-reviewed rehabilitation journal.

http://bit.ly/2BFPFmq

Can a tool developed for industry be used to assess fatigue risk in medical rotas? A pilot study of foundation doctors rotas in a tertiary centre

Objectives

To determine the feasibility and ease of using a pre-existing health and safety executive fatigue risk calculator to assess doctors' rotas.

Design

Observational.

Setting

A large tertiary-referral teaching hospital in the UK.

Participants

95 anonymised foundation years 1 and 2 rotas in General Medicine, General Surgery and Emergency Medicine covering a 4-month period. All rotas provided by rota coordinators were included and assessed.

Interventions

Rotas were assessed for two indices: relative risk of fatigue-related errors compared with a '2-day, two-night, four-off' shift pattern and percentage chance of a high score on a standardised sleepiness scale.

Primary and secondary outcome measures

Fatigue index (percentage chance of a high score on a standardised sleepiness scale) and risk index (relative risk of fatigue-related errors compared with a '2-day, two-night, four-off' shift pattern) of all shifts on all rotas.

Results

Nearly half of all shifts demonstrated increased risk of fatigue-related errors and increased probability of high levels of sleepiness. There was significant interspeciality variation in both indices. These results are based on rotas as opposed to 'work as done' and are therefore likely to slightly universally underestimate actual fatigue risks.

Conclusions

This preliminary study demonstrates that this tool can be used to compare rotas and guide rota design to minimise risk wherever possible. The calculator guidance clearly states there is no 'ideal risk' but that values should be minimised, and a maximum fatigue risk agreed which is deemed acceptable given the nature of work undertaken. This study is intended to demonstrate that fatigue can and should be considered during rota design. We do not suggest that it is used to hold either individuals or organisations to account as there is no evidence for it being used in this way. Further work should assess the practicality of designing medical rotas using this tool to minimise fatigue risk.

http://bit.ly/2TXRPoV

PROFIT, a PROspective, randomised placebo controlled feasibility trial of Faecal mIcrobiota Transplantation in cirrhosis: study protocol for a single-blinded trial

Introduction

Patients with advanced cirrhosis have enteric bacterial dysbiosis and translocation of bacteria and their products across the gut epithelial barrier. This culminates in systemic inflammation and endotoxaemia, inducing innate immune dysfunction which predisposes to infection, and development of complications such as bleeding, sepsis and hepatic encephalopathy. This feasibility study aims to assess the safety of administering faecal microbiota transplantion to patients with cirrhosis and explore the effect of the intervention on their prognosis by achieving restoration of a healthy gut microbiome.

Methods and analysis

A PROspective, randomised placebo controlled feasibility trial of Faecal mIcrobiota Transplantation is a single-centre, randomised, single-blinded, placebo-controlled study evaluating faecal microbiota transplantation (FMT) against placebo. Patients with advanced but stable cirrhosis with a Model for End-Stage Liver Disease score between 10 and 16 will be recruited. Twenty-four patients will be randomised to FMT plus standard of care (as per our institutional practice) and eight patients to placebo in a ratio of 3:1. Patients will be evaluated at baseline before the study intervention is administered and at 7, 30 and 90 days post-intervention to assess safety and adverse events. FMT/placebo will be administered into the jejunum within 7 days of baseline. The primary outcome measure will be safety and feasibility as assessed by recruitment rates, tolerability and safety of FMT treatment. Results will be disseminated via peer-reviewed journals and international conferences. The recruitment of the first patient occurred on 23 May 2018.

Ethics and dissemination

Research Ethics approval was given by the London South East Research Ethics committee (ref 17/LO/2081).

Trial registration number

NCT02862249 and EudraCT 2017-003629-13.

http://bit.ly/2TNUjWM

VaccHemInf project: protocol for a prospective cohort study of efficacy, safety and characterisation of immune functional response to vaccinations in haematopoietic stem cell transplant recipients

Introduction

Immune reconstitution after haematopoietic stem cell transplantation (HSCT) is a complex and dynamic process, varying from a state of nearly complete immunosuppression to an expected full immune recovery. Specific vaccination guidelines recommend reimmunisation after HSCT but data regarding vaccine efficacy in this unique population are scarce. New immune functional assays could enable prediction of vaccine response in the setting of HSCT.

Methods and analysis

A prospective, longitudinal single-centre cohort study of autologous and allogeneic HSCT recipients was designed in order to determine the vaccine response to five vaccine targets (pneumococcus, hepatitis B virus, Haemophilus Influenzae type b, tetanus and diphtheria) and to correlate it to immune function parameters. A workflow was set up to study serological response to vaccines and to describe the functional immune status of 100 HSCT recipients (50 autologous and 50 allogeneic) before and 3, 12 and 24 months after primary immunisation. At each time point, 'basic' immune status recording (serology, immunophenotyping of lymphocyte subsets by flow cytometry) will be assessed. The immune response will furthermore be evaluated before and 3 months after primary vaccination by two ex vivo immune functional assays assessing: (1) tumour necrosis factor alpha, interferon gamma production and host messenger RNA expression on whole-blood stimulation by lipopolysaccharide or Staphylococcus aureus enterotoxin B and (2) T-lymphocyte proliferation in response to a standard mitogen (phytohaemagglutinin) or to selected recall antigens. Reference intervals will be determined from a cohort of 30 healthy volunteers. This translational study will provide data describing vaccine response, immune functionality of HSCT recipients over time and will allow mapping HSCT recipients with regard to their immune function.

Ethics and dissemination

Ethical approval has been obtained from the institutional review board (no 69HCL17_0769). Results will be communicated at scientific meetings and submitted for publication in peer-reviewed journals.

Trial registration number

NCT03659773; Pre-results.

http://bit.ly/2BDbrat

Trial summary and protocol for a phase II randomised placebo-controlled double-blinded trial of Interleukin 1 blockade in Acute Severe Colitis: the IASO trial

Introduction

Acute severe ulcerative colitis (ASUC) is a severe manifestation of ulcerative colitis (UC) that warrants hospitalisation. Despite significant advances in therapeutic options for UC and in the medical management of steroid-refractory ASUC, the initial treatment paradigm has not changed since 1955 and is based on the use of intravenous corticosteroids. This treatment is successful in approximately 50% of patients but failure of this and subsequent medical therapy still occurs, with colectomy rates of up to 40% reported. The Interleukin 1 (IL-1) blockade in Acute Severe Colitis (IASO) trial aims to investigate whether antagonism of IL-1 signalling using anakinra in addition to intravenous corticosteroid treatment can improve outcomes in patients with ASUC.

Methods and analysis

IASO is a phase II, multicentre, two-arm (parallel group), randomised (1:1), placebo-controlled, double-blinded trial of short-duration anakinra in ASUC. Its primary outcome will be the incidence of medical (eg, infliximab/ciclosporin) or surgical rescue therapy (colectomy) within 10 days following the commencement of intravenous corticosteroid therapy. Secondary outcomes will include disease activity, time to clinical response, time to rescue therapy, colectomy incidence by day 98 post intravenous corticosteroids and safety. The trial aims to recruit 214 patients across 20 sites in the UK.

Ethics and dissemination

The trial has received approval from the Cambridge Central Research Ethics Committee (Ref: 17/EE/0347), the Health Research Authority (Ref: 201505) and Clinical Trials Authorisation from the Medicines and Healthcare products Regulatory Agency. We plan to present trial findings at scientific conferences and publish in high-impact peer-reviewed journals.

Trial registration number

ISRCTN43717130; EudraCT 2017-001389-10.

http://bit.ly/2TMpyRX

Burden of non-accidental mortality attributable to ambient temperatures: a time series study in a high plateau area of southwest China

Objective

To examine the total non-accidental mortality burden attributable to ambient temperatures and assess the effect modification of the burden by specific causes of death and individual characteristics in a high plateau area in southwest China.

Methods

Using daily mortality and meteorological data from 2009 to 2016, we applied a quasi-Poisson model combined with a distributed lag non-linear model to estimate the temperature–mortality association with the assessment of attributable fraction and number. We calculated attributable fractions and deaths with 95% empirical CIs (eCIs), that were due to cold and heat, defined as temperatures below and above the median temperature, and for mild and extreme temperatures, defined by cut-offs at the 2.5th and 97.5th temperature percentiles.

Results

We analysed 89 467 non-accidental deaths; 4131 were attributable to overall temperatures, with an attributable fraction of 4.75% (95% eCI 2.33% to 6.79%). Most of the mortality burden was caused by cold (4.08%; 0.86% to 7.12%), whereas the burden due to heat was low and non-significant (0.67%; –2.44% to 3.64%). Extreme cold (1.17%; 0.58% to 1.69%) was responsible for 24.6% (ie, 1.17% divided by 4.75%) of the total death burden. In the stratification analyses, attributable risk due to cold was higher for cardiovascular than respiratory disease (6.18% vs 3.50%). We found a trend of risk of increased death due to ambient temperatures with increasing age, with attributable fractions of 1.83%, 2.27% and 6.87% for age ≤64, 65–74 and ≥75 years old, respectively. The cold-related burden was slightly greater for females, farmers, ethnic minorities and non-married individuals than their corresponding categories.

Conclusions

Most of the burden of death was attributable to cold, and specific causes and individual characteristics might modify the mortality burden attributable to ambient temperatures. The results may help make preventive measures to confront climate change for susceptible population in this region.

http://bit.ly/2BFPF5U

Using specialist screening practitioners (SSPs) to increase uptake of bowel scope (flexible sigmoidoscopy) screening: results of a feasibility single-stage phase II randomised trial

Objective

To determine the feasibility of specialist screening practitioners (SSPs) offering patient navigation (PN) to facilitate uptake of bowel scope screening (BSS) among patients who do not confirm or attend their appointment.

Design

A single-stage phase II trial.

Setting

South Tyneside District Hospital, Tyne and Wear, England, UK.

Participants

Individuals invited for BSS at South Tyneside District Hospital during the 6-month recruitment period were invited to participate in the study.

Intervention

Consenting individuals were randomly assigned to either the PN intervention or usual care group in a 4:1 ratio. The intervention involved BSS non-attenders receiving a phone call from an SSP to elicit their reasons for non-attendance and offer educational, practical and emotional support as required. If requested by the patient, another BSS appointment was then scheduled.

Primary outcome measure

The number of non-attenders in the intervention group who were navigated and then rebooked and attended their new BSS appointment.

Secondary outcome measures

Barriers to BSS attendance, patient-reported outcomes including informed choice and satisfaction with BSS and the PN intervention, reasons for study non-participation, SSPs' evaluation of the PN process and a cost analysis.

Results

Of those invited to take part (n=1050), 152 (14.5%) were randomised into the study: PN intervention=109; usual care=43. Most participants attended their BSS appointment (PN: 79.8%; control: 79.1%) leaving 22 eligible for PN: only two were successfully contacted. SSPs were confident in delivering PN, but were concerned that low BSS awareness and information overload may have deterred patients from taking part in the study. Difficulty contacting patients was reported as a burden to their workload.

Conclusions

PN, as implemented, was not a feasible intervention to increase BSS uptake in South Tyneside. Interventions to increase BSS awareness may be better suited to this population.

Trial registration number

ISRCTN13314752; Results.

http://bit.ly/2TSSrvF

Comparison of the EQ-5D 3L and the SF-6D (SF-36) contemporaneous utility scores in patients with chronic kidney disease in Sri Lanka: a cross-sectional survey

Objectives

The aim of this study was to compare utility weights of EuroQoL-five-dimension-3 levels (EQ-5D-3L) and Short-Form six-dimension (SF-6D) in a representative cohort of patients with chronic kidney disease (CKD). A cost–utility analysis (CUA) is designed to report the change to costs required to achieve an estimated change to quality-adjusted life years (QALYs). The quality component of a QALY is measured by utility. Utility represents the preference of general population for a given health state. Classification systems of the multi-attribute utility instruments (MAUIs) are used to define these health states. Utility weights developed from different classification systems can vary and may affect the conclusions from CUAs.

Design

A community-based cross-sectional study.

Setting

Anuradhapura, a rural district in Sri Lanka.

Participants

A representative sample of 1096 patients with CKD, selected using the population-based CKD register, completed the EQ-5D-3L and SF-36. SF-6D was constructed from the SF-36 according to the published algorithm. The study assessed discrimination, correlation and differences across the two instruments.

Results

Study participants were predominantly male (62.6%). Mean EQ-5D-3L utility score was 0.540 (SD 0.35) compared with 0.534 (SD 0.09) for the SF-6D (p=0.588). The correlation (r) between the scores was 0.40 (p<0.001). Utility scores were significantly different in both males and females between the two tools, but there was no difference in age and educational categories. Both MAUI scores were significantly lower (p<0.001) among those who were in more advanced stages of the disease and the corresponding utility scores of the two instruments in different CKD stages were also significantly different (p<0.05). The largest effect size was seen among the patients on dialysis.

Conclusions

The correlation between the scores was moderate. SF-6D had the lowest floor and ceiling effect and was better at detecting different stages of the disease. Thus, based on the evidence presented in this study, SF-6D appears to be more appropriate to be used among patients with CKD.

http://bit.ly/2BDMVpM

Performance of biological mesh materials in abdominal wall reconstruction: study protocol for a randomised controlled trial

Introduction

Abdominal wall hernias are a common source of morbidity and mortality. The use of biological mesh has become an important adjunct in successful abdominal wall reconstruction. There are a variety of biological mesh products available; however, there is limited evidence supporting the use of one type over another. This study aims to compare the performance (eg, the rate of hernia recurrence) of either a crosslinked biological mesh product or a non-crosslinked product in patients undergoing abdominal wall reconstruction.

Methods and analysis

This is a single-centre, dual arm randomised controlled trial. Patients requiring abdominal wall reconstruction will be assessed for eligibility. Eligible patients will then undergo an informed consent process following by randomisation to either (1) crosslinked porcine dermis mesh (Permacol); or (2) non-crosslinked porcine dermis mesh (Strattice). These groups will be compared for the rate of hernia recurrence at 1 and 2 years as well as the rate of postoperative complications (eg, surgical site infections).

Ethics and dissemination

This study has been approved by the institution's research ethics board and registered with clinicaltrials.gov. All eligible participants will provide informed consent prior to randomization. The results of this study may help guide the choice of biologic mesh for this population. The results of this study will be published in peer-reviewed journals as well as national and international conferences.

Trial registration number

NCT02703662.

http://bit.ly/2TRykya

Systematic review of clinical outcome reporting in randomised controlled trials of burn care

Introduction

Systematic reviews collate trial data to provide evidence to support clinical decision-making. For effective synthesis, there must be consistency in outcome reporting. There is no agreed set of outcomes for reporting the effect of burn care interventions. Issues with outcome reporting have been identified, although not systematically investigated. This study gathers empirical evidence on any variation in outcome reporting and assesses the need for a core outcome set for burn care research.

Methods

Electronic searches of four search engines were undertaken from January 2012 to December 2016 for randomised controlled trials (RCTs), using medical subject headings and free text terms including 'burn', 'scald' 'thermal injury' and 'RCT'. Two authors independently screened papers, extracted outcomes verbatim and recorded the timing of outcome measurement. Duplicate outcomes (exact wording ± different spelling), similar outcomes (albumin in blood, serum albumin) and identical outcomes measured at different times were removed. Variation in outcome reporting was determined by assessing the number of unique outcomes reported across all included trials. Outcomes were classified into domains. Bias was reduced using five researchers and a patient working independently and together.

Results

147 trials were included, of which 127 (86.4%) were RCTs, 13 (8.8%) pilot studies and 7 (4.8%) RCT protocols. 1494 verbatim clinical outcomes were reported; 955 were unique. 76.8% of outcomes were measured within 6 months of injury. Commonly reported outcomes were defined differently. Numbers of unique outcomes per trial varied from one to 37 (median 9; IQR 5,13). No single outcome was reported across all studies demonstrating inconsistency of reporting. Outcomes were classified into 54 domains. Numbers of outcomes per domain ranged from 1 to 166 (median 11; IQR 3,24).

Conclusions

This review has demonstrated heterogeneity in outcome reporting in burn care research which will hinder amalgamation of study data. We recommend the development of a Core Outcome Set.

PROSPERO registration number

CRD42017060908.

http://bit.ly/2BEIcEf

Impact of repeated hospital accreditation surveys on quality and reliability, an 8-year interrupted time series analysis

Objective

To evaluate whether hospital re-accreditation improves quality, patient safety and reliability over three accreditation cycles by testing the accreditation life cycle model on quality measures.

Design

The validity of the life cycle model was tested by calibrating interrupted time series (ITS) regression equations for 27 quality measures. The change in the variation of quality over the three accreditation cycles was evaluated using the Levene's test.

Setting

A 650-bed tertiary academic hospital in Abu Dhabi, UAE.

Participants

Each month (over 96 months), a simple random sample of 10% of patient records was selected and audited resulting in a total of 388 800 observations from 14 500 records.

Intervention(s)

The impact of hospital accreditation on the 27 quality measures was observed for 96 months, 1-year preaccreditation (2007) and 3 years postaccreditation for each of the three accreditation cycles (2008, 2011 and 2014).

Main outcome measure(s)

The life cycle model was evaluated by aggregating the data for 27 quality measures to produce a composite score (Y_C) and to fit an ITS regression equation to the unweighted monthly mean of the series.

Results

The results provide some evidence for the validity of the four phases of the life cycle namely, the initiation phase, the presurvey phase, the postaccreditation slump and the stagnation phase. Furthermore, the life cycle model explains 87% of the variation in quality compliance measures (R²=0.87). The best-fit ITS model contains two significant variables (β₁ and β₃) (p≤0.001). The Levene's test (p≤0.05) demonstrated a significant reduction in variation of the quality measures (Y_C) with subsequent accreditation cycles.

Conclusion

The study demonstrates that accreditation has the capacity to sustain improvements over the accreditation cycle. The significant reduction in the variation of the quality measures (Y_C) with subsequent accreditation cycles indicates that accreditation supports the goal of high reliability.

http://bit.ly/2TSSrf9

Trends in resource use and effectiveness of ultrasound detection of fetal structural anomalies in France: a multiple registry-based study

Objective

To analyse trends in the number of ultrasound examinations in relation to the effectiveness of prenatal detection of birth defects using population-based data in France.

Design

A multiple registry-based study of time trends in resource use (number of ultrasounds) and effectiveness (proportion of cases prenatally diagnosed).

Setting

Three registries of congenital anomalies and claims data on ultrasounds for all pregnant women in France.

Participants

There were two samples of pregnant women. Effectiveness was assessed using data from three French birth defect registries. Resource use for ultrasound screening was based on the French national healthcare database.

Main outcome measures

The main outcome measures were prenatal diagnosis (effectiveness) and the average number of ultrasounds (resource use). Statistical analyses included linear and logistic regression models to assess trends in resource use and effectiveness of prenatal testing, respectively.

Results

The average number of ultrasound examinations per pregnancy significantly increased over the study period, from 2.47 in 2006 to 2.98 in 2014 (p=0.005). However, there was no significant increase in the odds of prenatal diagnosis. The probability of prenatal diagnosis was substantially higher for cases associated with a chromosomal anomaly (91.2%) than those without (51.8%). However, there was no evidence of an increase in prenatal detection of either over time.

Conclusions

The average number of ultrasound examinations per pregnancy increased over time, whereas the probability of prenatal diagnosis of congenital anomalies did not. Hence, there is a need to implement policies such as high-quality training programmes which can improve the efficiency of ultrasound examinations for prenatal detection of congenital anomalies.

http://bit.ly/2BE37Ya

Quality of reporting of outcomes in trials of therapeutic interventions for pressure ulcers in adults: a protocol for a systematic survey

Pressure ulcers (PUs) have a high incidence, especially in hospital units. Randomised clinical trials (RCTs) of therapeutic interventions for PU should include a clear description of the outcomes and results to enhance transparency and replicability.

Objectives

The primary objective of this study is to assess the completeness of the descriptions of the outcomes of therapeutic interventions in RCTs in adult patients with PU. The secondary objectives are to evaluate the types of reported primary outcomes, measurement methods or tools used to evaluate the outcomes and the results of reported outcomes.

Methods

We will conduct a systematic survey of RCTs published from January 2006 to April 2018. The selection process of the studies will be done in two stages of screening: title and abstract, and full text revision, always by two researchers independently. The completeness of the outcome will be assessed according to five criteria: domain (outcome title), specific measurement or technique/instrument used, specific metric or format of the outcome data that will be used for analysis, method of aggregation (how data from each group will be summarised) and time-points that will be used for analysis. The quality of the results of the outcome will be classified as either complete, incomplete or unreported. We will conduct a descriptive analysis of the number, type and degrees of outcome specification in the included RCTs. The frequency of categories in each domain of the outcomes will also be reported. The median and IQR will be estimated for each element of the specified outcome (out of five).

Ethics and dissemination

This will be the first systematic assessment of the outcomes of therapeutic interventions used for pressure ulcers. After completion, this review will be submitted to a peer-reviewed journals.

http://bit.ly/2TMpykV

Methemoglobinaemia with chronic phenazopyridine ingestion

http://bit.ly/2V2QXiQ

Neuroblastoma with an unusual ovarian metastasis in a 5-year-old girl

Neuroblastoma metastasizing to the ovary is rare. We report the 10th case and review the scarce literature. A 5-year-old girl with stage M neuroblastoma presented with an upper abdominal and a pelvic mass. Evaluation after induction showed very good tumour response with three remaining localisations: two abdominal and one pelvic. At gross total resection, the pelvic mass appeared to be the enlarged and abnormal right ovary and was removed completely. Pathology showed an ovarian metastasis. On completion of her postoperative treatment, she achieved complete remission. Literature review showed that underdiagnosing of ovarian metastasis in neuroblastoma is very likely.

http://bit.ly/2EbN6Kw

Liver transplant, toxoplasmosis and kidney stones: connecting the dots

http://bit.ly/2EfL6RB

MLL rearranged acute lymphoblastic leukaemia presenting as a maxillary sinus mass with a discordant immunophenotypic profile from the bone marrow

We describe an unusual case of pre-B lymphoblastic leukaemia presenting with a unilateral maxillary sinus mass in which biopsies of the primary mass and the bone marrow demonstrated conflicting immunophenotyping results. The extramedullary mass was consistent with a precursor B-cell malignancy, while the bone marrow was initially reported as a possible mature B-cell malignancy. The treatments for the two are fundamentally different, which necessitated a delay in the initiation of his chemotherapy until a clear diagnosis was made. Mixed lineage leukaemia gene rearrangement was confirmed by fluorescence in situ hybridisation in both the primary mass and bone marrow, which unified the diagnosis as pre-B acute lymphoblastic leukaemia given the common cytogenetic feature.

http://bit.ly/2V7LE1J

Plasma alpha‐synuclein detected by single molecule array is increased in PD

Abstract

We utilized ultrasensitive single molecule technology to measure plasma alpha‐synuclein in 221 subjects (51 controls, 170 PD). Plasma alpha‐synuclein levels were significantly higher in PD than controls (15506.3 vs. 13057.0 pg/mL, P = 0.037), adjusting for age and gender. In PD, alpha‐synuclein levels did not vary by H&Y stage or UPDRS motor scores but were significantly higher in PD patients with poorer cognition (MMSE ≤ 25) than controls (P = 0.016, Bonferroni corrected P = 0.047). Alpha‐synuclein levels quantified using ultrasensitive single molecule technology discriminate PD from controls and correlate with cognitive severity. These preliminary findings require independent validation to determine the utility of this assay.

http://bit.ly/2BzKrIY

Make EMS Week a year round celebration

Instead of relegating celebration to a single week of May consider how to recognize the accomplishments of EMS all year long.

http://bit.ly/2GM9Cvd

How far will the Voyager® take us?

CNS Oncology, Ahead of Print.


http://bit.ly/2SAY715

Influence of stanozolol administration together with resistance training on thyroid and some steroid hormones in male rats

Abstract

Abuse of anabolic–androgenic steroids (AASs) can lead to numerous detrimental health effects on body systems. With the increased self-administration of these steroids during the last decades, endocrine modifications and hormonal alterations associated with them have become an important clinical issue. The purpose of this research was to study the influence of 8-week injections of different doses of stanozolol (ST) along with resistance training (RT) on the levels of thyroid and some steroid hormones. Twenty-four male Wistar rats were divided into four groups, equally: group 1, untrained + normal saline; group 2, RT + normal saline; group 3, RT + ST (2 mg/kg b.w.); and group 4, RT + ST (5 mg/kg b.w.). The exercise protocol consisted of three training sessions weekly by 5 repetitions/3 sets of stepping onto the ladder for 8 weeks. Weight was loaded at the tail of each rat. Blood concentrations of T₃, T₄, FT₃, FT_4, TSH, testosterone, and dihydrotestosterone were determined by immunoassay methods. TSH concentration decreased significantly in groups 3 and 4 as compared to control group and group 2. Significant increment of FT₃ concentration was also observed in group 4 relative to groups 1 and 2. Dihydrotestosterone and testosterone concentrations decreased in groups 3 and 4 relative to controls, but the decrease was only statistically significant between groups 4 and 1. Moreover, exercise alone and also stanozolol treatment plus exercise induced no significant alteration on plasma concentrations of T₄, T₃, and FT₄ relative to controls. Current data show that ST treatment together with RT affects the levels of TSH, FT₃, dihydrotestosterone, and testosterone, which should be considered in pathophysiological outcomes of AAS abuse.

http://bit.ly/2By4F5Z

Gallic acid reduces inflammatory cytokines and markers of oxidative damage in a rat model of estradiol-induced polycystic ovary

Abstract

Hormonal disorders, oxidative stress, and inflammation in ovarian tissue cause ovulation failure in women with polycystic ovary syndrome. Considering the antioxidant properties of gallic acid (GA), the aim of this study was to investigate the effect of GA on pro-inflammatory cytokines, antioxidant enzyme activity, and DNA oxidative damage of ovarian tissue in a rat model of estradiol-induced polycystic ovary (PCO). In this experimental study, 32 female Wistar rats were divided into four groups. These included control (saline solution, orally), PCO+saline (estradiol valerate + saline solution, orally), PCO+GA50, and PCO+GA100 (estradiol valerate +50 and 100 mg/kg gallic acid, orally), respectively. The PCO model was induced by a single intramuscular injection of estradiol valerate (EV, 4 mg/kg). Twenty-four days after PCO modeling, tissue concentration of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) and also the activity level of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), malondialdehyde (MDA), and 8-oxo-2′-deoxyguanosine (8-OHdG) in ovarian tissue were measured through ELISA technique. Compared with the PCO+saline, in the GA-treated group, the concentration of TNF-α, IL-1β, and IL-6 in a dose-dependent manner significantly decreased (p > 0.05). In addition, the activity level of SOD, CAT, and GPX enzymes significantly increased (p < 0.05), while the amount of MDA and 8-OHdG significantly decreased (p > 0.05) in a dose-dependent manner. GA is an anti-inflammatory and an antioxidant polyphenol which reduces the concentration of inflammatory cytokines, oxidative stress, lipid peroxidation, and DNA oxidative damage of ovarian tissue in a rat's model of PCO.

http://bit.ly/2TW7a9u

Pathology, isolation and characterisation of virulent and diverse Mannheimia haemolytica and Pasteurella multocida associated with fatal pneumonia in sheep, Rajasthan, India

Abstract

Pneumonia, a major sheep disease, causes high mortality among affected animals predominantly the lambs. It is caused by a number of microbes including Mannheimia haemolytica/Pasteurella multocida. It was aimed to explore the pathology in the lungs due to pneumonia, and to isolate and characterise the virulent M. haemolytica/P. multocida strains. The lung tissues and heart blood specimens were collected by necropsy of sheep (n = 96). These samples were used for isolation and characterisation of M. haemolytica/P. multocida. Moreover, the fresh and square-shaped lung pieces were also taken to perform the histopathological analysis. Grossly, the petechial and ecchymotic haemorrhages, congestion and consolidation in lung lobes were observed at necropsy. Pneumonia was diagnosed as acute fibrinous-bronchopneumonia (36), suppurative chronic bronchopneumonia (10), acute interstitial pneumonia (32) and acute pulmonary congestion (18) based on histological lesions. Bacterial isolation recovered M. haemolytica alone or along with P. multocida and/or Bibersteinia trehalosi identified by phenotypic characters and sequencing of 16S rRNA. Haemolytic colonies were documented to carry the PHSSA, plpE and Rpt2 genes. P. multocida identification at species level was carried out by KMT1 gene detection. These isolates were noted to carry the capsule types A (hyaD-hyaC gene) and D (dcbF gene) and outer membrane protein genes ompH and omp87. Sequencing revealed nucleotide variability in Rpt2, ompH and omp87 genes.We highlighted the occurrence of fatal ovine pneumonic pasteurellosis/mannheimiosis caused and/or complicated by virulent M. haemolytica/P. multocida strains.

http://bit.ly/2BE3VfL

The stem cell markers expression CD44v6 and podoplanin in lip cancer: clinical significance

Abstract

This study aimed to analyze the immunoexpression of cancer stem cell markers, CD44v6, and podoplanin in 91 patients with lip squamous cell carcinomas (LSCC). The immunostaining of podoplanin and CD44v6 was evaluated in ten high-power fields (× 400 magnification) at the invasive front of LSCC, using a semi-quantitative score method. Chi-square test or Fisher's exact test was used to verify the association of podoplanin and CD44v6 expressions with clinicopathologic variables. Spearman's correlation test was used to analyze the correlation between the two antibodies in lip cancer. Disease-free survival probabilities in 5 and 10 years were estimated according to the Kaplan-Meier method and compared using the log-rank test. The independent effects of the significant variables were analyzed by Cox proportional hazards regression model. A strong podoplanin expression was observed in the membrane and cytoplasm of most lip tumor cells, and this was inversely associated with locoregional recurrence (p = 0.028) and with histopathological grade of malignancy (p = 0.026). Additionally, CD44v6 immunostaining was strongly expressed in the membrane of tumor cells in 95.4% of the LSCC. Patients with strong membranous (p = 0.016) or strong cytoplasmic (p = 0.030) podoplanin-positive tumors resulted in significantly better disease-free survival than those who had podoplanin weak/negative tumors, confirming podoplanin expression as a favorable independent prognostic factor. Podoplanin and CD44v6 were strongly expressed by tumor cells and podoplanin immunoexpression can help to determine lip cancer patients with lower risk for disease recurrence.

http://bit.ly/2Edcqjv

PDK1 mediates NOTCH1-mutated head and neck squamous carcinoma vulnerability to therapeutic PI3K/mTOR inhibition

Purpose: Head and neck squamous cell carcinoma (HNSCC) is driven largely by the loss of tumor suppressor genes, including NOTCH1, but lacks a biomarker-driven targeted therapy. Although the PI3K/mTOR pathway is frequently altered in HNSCC, the disease has modest clinical response rates to PI3K/mTOR inhibitors and lacks validated biomarkers of response. We tested the hypothesis that an unbiased pharmacogenomics approach to PI3K/mTOR pathway inhibitors would identify novel, clinically relevant molecular vulnerabilities in HNSCC with loss of tumor suppressor function. Methods: We assessed the degree to which responses to PI3K/mTOR inhibitors are associated with gene mutations in 59 HNSCC cell lines. Apoptosis in drug-sensitive cell lines was confirmed in vitro and in vivo. NOTCH1 pathway components and PDK1 were manipulated with drugs, gene editing, knockdown, and overexpression. Results: PI3K/mTOR inhibition caused apoptosis and decreased colony numbers in HNSCC cell lines harboring NOTCH1 loss-of-function mutations (NOTCH1 MUT) and reduced tumor size in subcutaneous and orthotopic xenograft models. In all cell lines, NOTCH1MUT was strongly associated with sensitivity to six PI3K/mTOR inhibitors. NOTCH1 inhibition or knockout increased NOTCH1WT HNSCC sensitivity to PI3K/mTOR inhibition. PDK1 levels dropped following PI3K/mTOR inhibition in NOTCH1MUT but not NOTCH1WT HNSCC, and PDK1 overexpression rescued apoptosis in NOTCH1MUT cells. PDK1 and AKT inhibitors together caused apoptosis in NOTCH1WT HNSCC but had little effect as single agents. Conclusion: Our findings suggest that NOTCH1MUT predicts response to PI3K/mTOR inhibitors, which may lead to the first biomarker-driven targeted therapy for HNSCC, and that targeting PDK1 sensitizes NOTCH1WT HNSCC to PI3K/mTOR pathway inhibitors.

http://bit.ly/2X6w4VK

Targeted assessment of G0S2 methylation identifies a rapidly recurrent, routinely fatal molecular subtype of adrenocortical carcinoma

Purpose: Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with few therapies; however, patients with locoregional disease have variable outcomes. The Cancer Genome Atlas project on ACC (ACC-TCGA) identified that cancers of patients with homogeneously rapidly recurrent or fatal disease bear a unique CpG island hypermethylation phenotype, "CIMP-high." We sought to identify a biomarker that faithfully captures this subgroup. Experimental Design: We analyzed ACC-TCGA data to characterize differentially regulated biological processes, and identify a biomarker that is methylated and silenced exclusively in CIMP-high ACC. In an independent cohort of 114 adrenocortical tumors (80 treatment-naive primary ACC, 22 adrenocortical adenomas, and 12 non-naive/non-primary ACC), we evaluated biomarker methylation by a restriction digest/qPCR-based approach, validated by targeted bisulfite sequencing. We evaluated expression of this biomarker and additional prognostic markers by qPCR. Results: We show that CIMP-high ACC is characterized by upregulation of cell cycle and DNA damage response programs, and identify that hypermethylation and silencing of G0S2 distinguishes this subgroup. We confirmed G0S2 hypermethylation and silencing is exclusive to 40% of ACC, and independently predicts shorter disease-free and overall survival (median 14 and 17 months, respectively). Finally, G0S2 methylation combined with validated molecular markers (BUB1B-PINK1) stratifies ACC into three groups, with uniformly favorable, intermediate, and uniformly dismal outcomes. Conclusions: G0S2 hypermethylation is a hallmark of rapidly recurrent or fatal ACC, amenable to targeted assessment using routine molecular diagnostics. Assessing G0S2 methylation is straightforward, feasible for clinical decision-making, and will enable the direction of efficacious adjuvant therapies for patients with aggressive ACC.

http://bit.ly/2S20e8Z

Phase I Study of the Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Navoximod (GDC-0919) Administered with PD-L1 Inhibitor (Atezolizumab) in Advanced Solid Tumors

Purpose: IDO1 induces immune suppression in T cells through L-tryptophan (Trp) depletion and kyneurinine (Kyn) accumulation in the local tumor microenvironment, suppressing effector T-cells and hyperactivating Tregs. Navoximod is an investigational small molecule inhibitor of IDO1. This Phase I study evaluated safety, tolerability, PK and PD of navoximod in combination with atezolizumab, a PD-L1 inhibitor, in patients with advanced cancer. Experimental Design: The study consisted of a 3+3 dose-escalation stage (n=66) and a tumor-specific expansion stage (n=92). Navoximod was given orally every 12 hours (q12h) continuously for 21 consecutive days of each cycle with the exception of Cycle 1, where navoximod administration started on Day -1 to characterize PK. Atezolizumab was administered by IV infusion 1200 mg q3w on Day 1 of each cycle. Results: Patients (n=157) received navoximod at 6 dose levels (50-1000 mg) in combination with atezolizumab. MAD was 1000 mg BID; the MTD was not reached. Navoximod demonstrated a linear PK profile, and plasma Kyn generally decreased with increasing doses of navoximod. The most common treatment-related AEs were fatigue (22%), rash (22%), and chromaturia (20%). Activity was observed at all dose levels in various tumor types (melanoma, pancreatic, prostate, ovarian, HNSCC, cervical, neural sheath, NSCLC, TNBC, RCC, UBC): 6 (9%) dose escalation patients achieved PR, 10 (11%) expansion patients achieved PR or CR. Conclusions: The combination of navoximod and atezolizumab demonstrated acceptable safety, tolerability, and PK for patients with advanced cancer. Although activity was observed, there was no clear evidence for benefit of adding navoximod to atezolizumab.

http://bit.ly/2X6B5gU

(Not Giving Up) The Marathon Race of MET Targeting Therapy - Are We There Yet?

Among various MET aberrations, MET amplification and METex14 have emerged as valid predictive biomarkers for MET inhibition. Despite challenges that have limited the development of MET inhibitors, we can learn from the latest efforts in biomarker-based therapy to better identify the patients who will benefit from treatment with these agents.

http://bit.ly/2S20apL

ATR inhibition potentiates the radiation induced inflammatory tumour microenvironment

Purpose: ATR inhibitors (ATRi) are in early phase clinical trials and have been shown to sensitise to chemotherapy and radiotherapy preclinically. No data have been published about the effect of these drugs on the tumor microenvironment. Experimental Design: We used an immunocompetent mouse model of HPV-driven malignancies to investigate the ATR inhibitor AZD6738 in combination with fractionated radiation (RT). Gene expression analysis and flow cytometry were performed post-therapy. Results: Significant radiosensitization to RT by ATRi was observed alongside a marked increase in immune cell infiltration. We identified increased numbers of CD3+ and NK cells but most of this infiltrate was composed of myeloid cells. ATRi plus radiation produced a gene expression signature matching a type I/II interferon response with upregulation of genes playing a role in nucleic acid sensing. Increased MHCI levels were observed on tumor cells, with transcript level data indicating increased antigen processing and presentation within the tumor. Significant modulation of cytokine gene expression (particularly CCL2, CCL5 and CXCL10) was found in vivo, with in vitro data indicating CCL3, CCL5 and CXCL10 are produced from tumor cells after ATRi + RT. Conclusions: We hypothesise that DNA damage by ATRi and RT leads to an interferon response through activation of nucleic acid sensing pathways. This triggers increased antigen presentation and innate immune cell infiltration. Further understanding of this combination on the immune response may allow modulation of these effects to maximise tumor control through anti-tumor immunity.

http://bit.ly/2X6B0tC

Tumor Burden Affects Efficacy of Combination Immunotherapy [Research Watch]

Combined CTLA4 and PD-L1 blockade hinders antitumor immunity in patients with low tumor burden.

http://bit.ly/2DJ8x4d

Chromosome-Wide Evolution and Sex Determination in the Three-Sexed Nematode Auanema rhodensis

Trioecy, a mating system in which males, females and hermaphrodites co-exist, is a useful system to investigate the origin and maintenance of alternative mating In the trioecious nematode Auanema rhodensis, males have one X chromosome (XO), whereas females and hermaphrodites have two (XX). The female versus hermaphrodite sex determination mechanisms have remained elusive. In this study, RNA-seq analyses show a 20% difference between the L2 hermaphrodite and female gene expression profiles. RNAi experiments targeting the DM (doublesex/mab-3) domain transcription factor dmd-10/11 suggest that the hermaphrodite sexual fate requires the upregulation of this gene. The genetic linkage map (GLM) shows that there is chromosome-wide heterozygosity for the X chromosome in F2 hermaphrodite-derived lines originated from crosses between two parental inbred strains. These results confirm the lack of recombination of the X chromosome in hermaphrodites, as previously reported. We also describe conserved chromosome elements (Nigon elements), which have been mostly maintained throughout the evolution of Rhabditina nematodes. The seven-chromosome karyotype of A. rhodensis, instead of the typical six found in other rhabditine species, derives from fusion/rearrangements events involving three Nigon elements. The A. rhodensis X chromosome is the smallest and most polymorphic with the least proportion of conserved genes. This may reflect its atypical mode of father-to-son transmission and its lack of recombination in hermaphrodites and males. In conclusion, this study provides a framework for studying the evolution of chromosomes in rhabditine nematodes, as well as possible mechanisms for the sex determination in a three-sexed species.

http://bit.ly/2X6vQhm

The m6A-Binding Protein YTHDF1 Mediates Immune Evasion [Research Watch]

Loss of the mRNA m⁶A-binding protein YTHDF1 in dendritic cells enhances antitumor immunity.

http://bit.ly/2DHMbQJ

TP53 Mutations Are Immunogenic in Epithelial Cancer [Research Watch]

Mutant p53-specific T cells were isolated from patients with metastatic epithelial cancers.

http://bit.ly/2SE1Jiw

Bacterial Mix Enhances Immunotherapy Response [News in Brief]

Anti–PD-1, anti-CTLA4 therapies work better in mice after inoculation of 11 microbial strains.

http://bit.ly/2SFj2A2

Targeting Alterations in the RAF-MEK Pathway [Review]

The MAPK pathway is one of the most commonly mutated oncogenic pathways in cancer. Although RAS mutations are the most frequent MAPK alterations, less frequent alterations in downstream components of the pathway, including the RAF and MEK genes, offer promising therapeutic opportunities. In addition to BRAF^V600 mutations, for which several approved therapeutic regimens exist, other alterations in the RAF and MEK genes may provide more rare, but tractable, targets. However, recent studies have illustrated the complexity of MAPK signaling and highlighted that distinct alterations in these genes may have strikingly different properties. Understanding the unique functional characteristics of specific RAF and MEK alterations, reviewed herein, will be critical for developing effective therapeutic approaches for these targets.

Significance: Alterations in the RAF and MEK genes represent promising therapeutic targets in multiple cancer types. However, given the unique and complex signaling biology of the MAPK pathway, the diverse array of RAF and MEK alterations observed in cancer can possess distinct functional characteristics. As outlined in this review, understanding the key functional properties of different RAF and MEK alterations is fundamental to selecting the optimal therapeutic approach.

http://bit.ly/2DO5M1Q