Definitive chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) for advanced cervical esophageal cancer

Abstract

Background

Recently, definitive chemoradiotherapy (dCRT) has become one of the essential treatment strategies for esophageal squamous cell carcinoma (ESCC) and has been especially gaining prevalence for cervical ESCC to preserve the larynx. Our department recently introduced dCRT concomitant with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) for treating advanced cervical ESCC. This study aims to assess the safety and outcomes of DCF-R in patients with advanced cervical ESCC.

Methods

We retrospectively assessed 11 patients with advanced cervical ESCC (clinical stage: II–IV, including T4b and/or M1 lymph node) who received DCF-R as the first-line treatment between December 2010 and February 2015.

Results

Our patient cohort comprised 8 males and 3 females (median age 68 years; range 54–76 years). The pretreatment clinical stage included stage II (1), stage III (7), and stage IV (3) cases [including 3 patients with T4b (2 trachea and 1 thyroid) and 3 patients with M1 lymph node]. We attained complete response (CR) in 10 patients and stable disease in 1 patient. Of 10 patients with CR, 5 experienced recurrence and 5 continued exhibiting CR. Furthermore, grade 3 or more adverse events included leucopenia (91%), neutropenia (91%), febrile neutropenia (45%), and pharyngeal pain (55%). While the 2-year overall survival rate was 72%, the 2-year recurrent-free survival rate was 64%, respectively.

Conclusions

DCF-R treatment for advanced cervical esophageal cancer could be completed by the careful administration; although a strong blood toxicity might occur, this treatment may provide the chance to obtain favorable prognosis with larynx preservation.

https://ift.tt/2ymx1kD

FDA Approves First Generic Versions of Suboxone Sublingual Film, Which May Increase Access to Treatment for Opioid Dependence

June 14, 2018 -- The U.S. Food and Drug Administration today approved the first generic versions of Suboxone (buprenorphine and naloxone) sublingual film (applied under the tongue) for the treatment of opioid dependence. "The FDA is taking new...

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Fighting breast cancer stem cells through the immune-targeting of the xCT cystine–glutamate antiporter

Abstract

Tumor relapse and metastatic spreading act as major hindrances to achieve complete cure of breast cancer. Evidence suggests that cancer stem cells (CSC) would function as a reservoir for the local and distant recurrence of the disease, due to their resistance to radio- and chemotherapy and their ability to regenerate the tumor. Therefore, the identification of appropriate molecular targets expressed by CSC may be critical in the development of more effective therapies. Our studies focused on the identification of mammary CSC antigens and on the development of CSC-targeting vaccines. We compared the transcriptional profile of CSC-enriched tumorspheres from an Her2⁺ breast cancer cell line with that of the more differentiated parental cells. Among the molecules strongly upregulated in tumorspheres we selected the transmembrane amino-acid antiporter xCT. In this review, we summarize the results we obtained with different xCT-targeting vaccines. We show that, despite xCT being a self-antigen, vaccination was able to induce a humoral immune response that delayed primary tumor growth and strongly impaired pulmonary metastasis formation in mice challenged with tumorsphere-derived cells. Moreover, immunotargeting of xCT was able to increase CSC chemosensitivity to doxorubicin, suggesting that it may act as an adjuvant to chemotherapy. In conclusion, our approach based on the comparison of the transcriptome of tumorspheres and parental cells allowed us to identify a novel CSC-related target and to develop preclinical therapeutic approaches able to impact on CSC biology, and therefore, hampering tumor growth and dissemination.

https://ift.tt/2MqJYNf

Spatial relationship of 2-deoxy-2-[ 18 F]-fluoro-D-glucose positron emission tomography and magnetic resonance diffusion imaging metrics in cervical cancer

Abstract

Background

This study investigated the spatial relationship of 2-deoxy-2-[¹⁸F]-fluoro-D-glucose positron emission tomography ([¹⁸F]FDG-PET) standardized uptake values (SUVs) and apparent diffusion coefficients (ADCs) derived from magnetic resonance (MR) diffusion imaging on a voxel level using simultaneously acquired PET/MR data.

We performed an institutional retrospective analysis of patients with newly diagnosed cervical cancer who received a pre-treatment simultaneously acquired [¹⁸F]FDG-PET/MR. Voxel SUV and ADC values, and global tumor metrics including maximum SUV (SUV_max), mean ADC (ADC_mean), and mean tumor-to-muscle ADC ratio (ADC_T/M) were compared. The impacts of histology, grade, and tumor volume on the voxel SUV to ADC relationship were also evaluated. The potential prognostic value of the voxel SUV/ADC relationship was evaluated in an exploratory analysis using Kaplan-Meier/log-rank and univariate Cox analysis.

Results

Seventeen patients with PET/MR scans were identified. There was a significant inverse correlation between SUV_max and ADC_mean, and SUV_max and ADC_T/M. In the voxelwise analysis, squamous cell carcinomas (SCCAs) and poorly differentiated tumors showed a consistent significant inverse correlation between voxel SUV and ADC values; adenocarcinomas (AdenoCAs) and well/moderately differentiated tumors did not. The strength of the voxel SUV/ADC correlation varied with metabolic tumor volume (MTV). On log-rank analysis, the correlation between voxel SUV/ADC values was prognostic of disease-free survival (DFS).

Conclusions

In this hypothesis-generating study, a consistent inverse correlation between voxel SUV and ADC values was seen in SCCAs and poorly differentiated tumors. On univariate statistical analysis, correlation between voxel SUV and ADC values was prognostic for DFS.

https://ift.tt/2sYmerF

PET imaging of 68 Ga-NODAGA-RGD, as compared with 18 F-fluorodeoxyglucose, in experimental rodent models of engrafted glioblastoma

Abstract

Background

Tracers triggering αvβ3 integrins, such as certain RGD-containing peptides, were found promising in previous pilot studies characterizing high-grade gliomas. However, only limited comparisons have been performed with current PET tracers. This study aimed at comparing the biodistribution of ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) with that of ⁶⁸Ga-NODAGA-RGD, an easily synthesized monomeric RGD compound with rapid kinetics, in two different rodent models of engrafted human glioblastoma.

Methods

Nude rodents bearing human U87-MG glioblastoma tumor xenografts in the flank (34 tumors in mice) or in the brain (5 tumors in rats) were analyzed. Kinetics of ⁶⁸Ga-NODAGA-RGD and of ¹⁸F-FDG were compared with PET imaging in the same animals, along with additional autohistoradiographic analyses and blocking tests for ⁶⁸Ga-NODAGA-RGD.

Results

Both tracers showed a primary renal route of clearance, although with faster clearance for ⁶⁸Ga-NODAGA-RGD resulting in higher activities in the kidneys and bladder. The tumor activity from ⁶⁸Ga-NODAGA-RGD, likely corresponding to true integrin binding (i.e., suppressed by co-injection of a saturating excess of unlabeled RGD), was found relatively high, but only at the 2^nd hour following injection, corresponding on average to 53% of total tumor activity. Tumor uptake of ⁶⁸Ga-NODAGA-RGD decreased progressively with time, contrary to that of ¹⁸F-FDG, although ⁶⁸Ga-NODAGA-RGD exhibited 3.4 and 3.7-fold higher tumor-to-normal brain ratios on average compared to ¹⁸F-FDG in mice and rat models, respectively. Finally, ex-vivo analyses revealed that the tumor areas with high ⁶⁸Ga-NODAGA-RGD uptake also exhibited the highest rates of cell proliferation and αv integrin expression, irrespective of cell density.

Conclusions

⁶⁸Ga-NODAGA-RGD has a high potential for PET imaging of glioblastomas, especially for areas with high integrin expression and cell proliferation, although PET recording needs to be delayed until the 2^nd hour following injection in order to provide sufficiently high integrin specificity.

https://ift.tt/2JCP0s6

The value of 99m Tc-MAA SPECT/CT for lung shunt estimation in 90 Y radioembolization: a phantom and patient study

Abstract

Background

A major toxicity concern in radioembolization therapy of hepatic malignancies is radiation-induced pneumonitis and sclerosis due to hepatopulmonary shunting of ⁹⁰Y microspheres. Currently, ^99mTc macroaggregated albumin (^99mTc-MAA) imaging is used to estimate the lung shunt fraction (LSF) prior to treatment. The aim of this study was to evaluate the accuracy/precision of LSF estimated from ^99mTc planar and SPECT/CT phantom imaging, and within this context, to compare the corresponding LSF and lung-absorbed dose values from ^99mTc-MAA patient studies. Additionally, LSFs from pre- and post-therapy imaging were compared.

Results

A liver/lung torso phantom filled with ^99mTc to achieve three lung shunt values was scanned by planar and SPECT/CT imaging with repeat acquisitions to assess accuracy and precision. To facilitate processing of patient data, a workflow that relies on SPECT and CT-based auto-contouring to define liver and lung volumes for the LSF calculation was implemented. Planar imaging-based LSF estimates for 40 patients, obtained from their medical records, were retrospectively compared with SPECT/CT imaging-based calculations with attenuation and scatter correction. Additionally, in a subset of 20 patients, the pre-therapy estimates were compared with ⁹⁰Y PET/CT-based measurements.

In the phantom study, improved accuracy in LSF estimation was achieved using SPECT/CT with attenuation and scatter correction (within 13% of the true value) compared with planar imaging (up to 44% overestimation). The results in patients showed a similar trend with planar imaging significantly overestimating LSF compared to SPECT/CT. There was no correlation between lung shunt estimates and the delay between ^99mTc-MAA administration and scanning, but off-target extra hepatic uptake tended to be more likely in patients with a longer delay. The mean lung absorbed dose predictions for the 28 patients who underwent therapy was 9.3 Gy (range 1.3–29.4) for planar imaging and 3.2 Gy (range 0.4–13.4) for SPECT/CT. For the patients with post-therapy imaging, the mean LSF from ⁹⁰Y PET/CT was 1.0%, (range 0.3–2.8). This value was not significantly different from the mean LSF estimate from ^99mTc-MAA SPECT/CT (mean 1.0%, range 0.4–1.6; p = 0.968), but was significantly lower than the mean LSF estimate based on planar imaging (mean 4.1%, range 1.2–15.0; p = 0.0002).

Conclusions

The improved accuracy demonstrated by the phantom study, agreement with ⁹⁰Y PET/CT in patient studies, and the practicality of using auto-contouring for liver/lung definition suggests that ^99mTc-MAA SPECT/CT with scatter and attenuation corrections should be used for lung shunt estimation prior to radioembolization.

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Functional Precision Medicine Identifies Novel Druggable Targets and Therapeutic Options in Head and Neck Cancer

Purpose: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with high mortality and a lack of targeted therapies. To identify and prioritize druggable targets, we performed genome analysis together with genome-scale siRNA and oncology drug profiling using low-passage tumor cells derived from a patient with treatment-resistant HPV-negative HNSCC.

Experimental Design: A tumor cell culture was established and subjected to whole-exome sequencing, RNA sequencing, comparative genome hybridization, and high-throughput phenotyping with a siRNA library covering the druggable genome and an oncology drug library. Secondary screens of candidate target genes were performed on the primary tumor cells and two nontumorigenic keratinocyte cell cultures for validation and to assess cancer specificity. siRNA screens of the kinome on two isogenic pairs of p53-mutated HNSCC cell lines were used to determine generalizability. Clinical utility was addressed by performing drug screens on two additional HNSCC cell cultures derived from patients enrolled in a clinical trial.

Results: Many of the identified copy number aberrations and somatic mutations in the primary tumor were typical of HPV(–) HNSCC, but none pointed to obvious therapeutic choices. In contrast, siRNA profiling identified 391 candidate target genes, 35 of which were preferentially lethal to cancer cells, most of which were not genomically altered. Chemotherapies and targeted agents with strong tumor-specific activities corroborated the siRNA profiling results and included drugs that targeted the mitotic spindle, the proteasome, and G₂–M kinases WEE1 and CHK1. We also show the feasibility of ex vivo drug profiling for patients enrolled in a clinical trial.

Conclusions: High-throughput phenotyping with siRNA and drug libraries using patient-derived tumor cells prioritizes mutated driver genes and identifies novel drug targets not revealed by genomic profiling. Functional profiling is a promising adjunct to DNA sequencing for precision oncology. Clin Cancer Res; 24(12); 2828–43. ©2018 AACR.

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Sequencing Pancreatic Juice: Squeezing the Most Out of Surveillance

Next-generation sequencing of pancreatic juice can detect and quantify tumor-promoting mutations, supporting imaging and cytology findings to predict the degree of dysplasia in patients at high risk for pancreatic cancer. Future studies are needed to optimize this approach and determine how it best fits into clinical practice. Clin Cancer Res; 24(12); 2713–5. ©2018 AACR.

See related article by Suenaga et al., p. 2963

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Revisiting Interleukin-12 as a Cancer Immunotherapy Agent

IL12 antitumor activities are mediated by the activation of T and natural killer (NK) lymphocytes to produce IFN. Systemically, recombinant IL12 has a narrow therapeutic window that favors local delivery, for instance, by gene therapy approaches. IL12 is a powerful partner in immunotherapy combinations with checkpoint inhibitors and adoptive T-cell transfer. Clin Cancer Res; 24(12); 2716–8. ©2018 AACR.

See related article by Hu et al., p. 2920

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Precision Oncology Decision Support: Current Approaches and Strategies for the Future

With the increasing availability of genomics, routine analysis of advanced cancers is now feasible. Treatment selection is frequently guided by the molecular characteristics of a patient's tumor, and an increasing number of trials are genomically selected. Furthermore, multiple studies have demonstrated the benefit of therapies that are chosen based upon the molecular profile of a tumor. However, the rapid evolution of genomic testing platforms and emergence of new technologies make interpreting molecular testing reports more challenging. More sophisticated precision oncology decision support services are essential. This review outlines existing tools available for health care providers and precision oncology teams and highlights strategies for optimizing decision support. Specific attention is given to the assays currently available for molecular testing, as well as considerations for interpreting alteration information. This article also discusses strategies for identifying and matching patients to clinical trials, current challenges, and proposals for future development of precision oncology decision support. Clin Cancer Res; 24(12); 2719–31. ©2018 AACR.

https://ift.tt/2sXbN7p

Higher Absolute Lymphocyte Counts Predict Lower Mortality from Early-Stage Triple-Negative Breast Cancer

Purpose: Tumor-infiltrating lymphocytes (TIL) in pretreatment biopsies are associated with improved survival in triple-negative breast cancer (TNBC). We investigated whether higher peripheral lymphocyte counts are associated with lower breast cancer–specific mortality (BCM) and overall mortality (OM) in TNBC.

Experimental Design: Data on treatments and diagnostic tests from electronic medical records of two health care systems were linked with demographic, clinical, pathologic, and mortality data from the California Cancer Registry. Multivariable regression models adjusted for age, race/ethnicity, socioeconomic status, cancer stage, grade, neoadjuvant/adjuvant chemotherapy use, radiotherapy use, and germline BRCA1/2 mutations were used to evaluate associations between absolute lymphocyte count (ALC), BCM, and OM. For a subgroup with TIL data available, we explored the relationship between TILs and peripheral lymphocyte counts.

Results: A total of 1,463 stage I–III TNBC patients were diagnosed from 2000 to 2014; 1,113 (76%) received neoadjuvant/adjuvant chemotherapy within 1 year of diagnosis. Of 759 patients with available ALC data, 481 (63.4%) were ever lymphopenic (minimum ALC <1.0 K/μL). On multivariable analysis, higher minimum ALC, but not absolute neutrophil count, predicted lower OM [HR = 0.23; 95% confidence interval (CI), 0.16–0.35] and BCM (HR = 0.19; CI, 0.11–0.34). Five-year probability of BCM was 15% for patients who were ever lymphopenic versus 4% for those who were not. An exploratory analysis (n = 70) showed a significant association between TILs and higher peripheral lymphocyte counts during neoadjuvant chemotherapy.

Conclusions: Higher peripheral lymphocyte counts predicted lower mortality from early-stage, potentially curable TNBC, suggesting that immune function may enhance the effectiveness of early TNBC treatment. Clin Cancer Res; 24(12); 2851–8. ©2018 AACR.

https://ift.tt/2JNcM0F

Anaplastic Lymphoma Kinase Mutation (ALK F1174C) in Small Cell Carcinoma of the Prostate and Molecular Response to Alectinib

Purpose: Small cell carcinoma of the prostate (SCCP) is an aggressive disease that can arise de novo or by transdifferentiation from prostate adenocarcinoma. Alterations in anaplastic lymphoma kinase (ALK) gene are involved in neuroblastoma, lung cancer, and other malignancies, but its role in SCCP has not been documented. We describe a patient with refractory de novo SCCP with ALK F1174C–activating mutation who obtained clinical benefit from treatment with ALK inhibitor.

Experimental Design: Next-generation sequencing (NGS) was used to analyze primary and circulating tumor DNA (ctDNA). Prostate cancer databases were queried for alterations in ALK gene, mRNA, and its impact in clinical outcomes. In vitro prostate cell line/organoid models were generated by lentiviral-mediated expression of ALK and ALK F1174C and assessed for response to ALK inhibitors crizotinib and alectinib.

Results: NGS analysis of the primary tumor and ctDNA of a 39-year-old patient with refractory SSCP identified ALK F1174C mutation. Treatment with second-generation ALK inhibitor alectinib resulted in radiographic stable disease for over 6 months, symptomatic improvement, and significant molecular response as reflected by declining ctDNA allele fraction. Analysis of prostate cancer datasets showed that ALK amplification was associated with poor outcome. In prostate cancer cells and organoids, ALK F1174C expression enhanced growth and induced expression of the neuroendocrine marker neuron-specific enolase. Alectinib was more effective than crizotinib in inhibiting ALK F1174C–expressing cell growth.

Conclusions: These findings implicate ALK-activating mutations in SCCP pathogenesis and suggest the therapeutic potential of targeting ALK molecular alterations in some patients with SCCP. Clin Cancer Res; 24(12); 2732–9. ©2018 AACR.

https://ift.tt/2taazFl

Endogenous Replication Stress Marks Melanomas Sensitive to CHEK1 Inhibitors In Vivo

Purpose: Checkpoint kinase 1 inhibitors (CHEK1i) have single-agent activity in vitro and in vivo. Here, we have investigated the molecular basis of this activity.

Experimental Design: We have assessed a panel of melanoma cell lines for their sensitivity to the CHEK1i GNE-323 and GDC-0575 in vitro and in vivo. The effects of these compounds on responses to DNA replication stress were analyzed in the hypersensitive cell lines.

Results: A subset of melanoma cell lines is hypersensitive to CHEK1i-induced cell death in vitro, and the drug effectively inhibits tumor growth in vivo. In the hypersensitive cell lines, GNE-323 triggers cell death without cells entering mitosis. CHEK1i treatment triggers strong RPA2 hyperphosphorylation and increased DNA damage in only hypersensitive cells. The increased replication stress was associated with a defective S-phase cell-cycle checkpoint. The number and intensity of pRPA2 Ser4/8 foci in untreated tumors appeared to be a marker of elevated replication stress correlated with sensitivity to CHEK1i.

Conclusions: CHEK1i have single-agent activity in a subset of melanomas with elevated endogenous replication stress. CHEK1i treatment strongly increased this replication stress and DNA damage, and this correlated with increased cell death. The level of endogenous replication is marked by the pRPA2Ser4/8 foci in the untreated tumors, and may be a useful marker of replication stress in vivo. Clin Cancer Res; 24(12); 2901–12. ©2018 AACR.

https://ift.tt/2JR159i

Exosome-Based Detection of EGFR T790M in Plasma from Non-Small Cell Lung Cancer Patients

Purpose: About 60% of non–small cell lung cancer (NSCLC) patients develop resistance to targeted epidermal growth factor receptor (EGFR) inhibitor therapy through the EGFR T790M mutation. Patients with this mutation respond well to third-generation tyrosine kinase inhibitors, but obtaining a tissue biopsy to confirm the mutation poses risks and is often not feasible. Liquid biopsies using circulating free tumor DNA (cfDNA) have emerged as a noninvasive option to detect the mutation; however, sensitivity is low as many patients have too few detectable copies in circulation. Here, we have developed and validated a novel test that overcomes the limited abundance of the mutation by simultaneously capturing and interrogating exosomal RNA/DNA and cfDNA (exoNA) in a single step followed by a sensitive allele-specific qPCR.

Experimental Design: ExoNA was extracted from the plasma of NSCLC patients with biopsy-confirmed T790M-positive (N = 102) and T790M-negative (N = 108) samples. The T790M mutation status was determined using an analytically validated allele-specific qPCR assay in a Clinical Laboratory Improvement Amendment laboratory.

Results: Detection of the T790M mutation on exoNA achieved 92% sensitivity and 89% specificity using tumor biopsy results as gold standard. We also obtained high sensitivity (88%) in patients with intrathoracic disease (M0/M1a), for whom detection by liquid biopsy has been particularly challenging.

Conclusions: The combination of exoRNA/DNA and cfDNA for T790M detection has higher sensitivity and specificity compared with historical cohorts using cfDNA alone. This could further help avoid unnecessary tumor biopsies for T790M mutation testing. Clin Cancer Res; 24(12); 2944–50. ©2018 AACR.

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Highlights of This Issue

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Improved Risk Stratification by Circulating Tumor Cell Counts in Pancreatic Cancer

Purpose: Pancreatic cancer is one of the most devastating diseases with a 5-year survival rate of 3% to 5%. Here, we investigated whether circulating tumor cells (CTC) may predict metastatic spread and survival in pancreatic cancer patients.

Experimental Design: In a prospective study, we enrolled 69 pancreatic cancer patients. In peripheral blood, CTCs were identified by MACS enrichment (anti-cytokeratin/anti-EpCam) and subsequent automated analysis after combined anti-cytokeratin/anti-CD45/DAPI staining. CTC results were correlated to established clinicopathologic risk factors, detection of disseminated tumor cells (DTC) in bone marrow, and clinical outcome (follow-up time: 48 months).

Results: Median patient survival was 11 months (0–48 months). Thirty-eight patients were male and 31 were female, and the majority received gemcitabine (58/69). CTCs were present in 23 of 69 patients (33.3%) ranging from 1 to 19 cells (17 with >1 CTC). Although clinicopathologic parameters and DTC status did not correlate with CTC incidence, progression-free survival (PFS) and overall survival (OS) were significantly reduced in CTC-positive patients in univariate (P = 0.009, PFS; P = 0.030, OS, both log rank) and multivariate analysis [HR = 4.543; confidence interval (CI), 1.549–13.329; P = 0.006, PFS; HR = 2.093; CI, 1.081–4.050; P = 0.028, OS, both Cox regression). Also within patients receiving chemotherapy, PFS was significantly reduced in CTC-positive patients in univariate (P = 0.013) and multivariate (HR = 4.203; CI, 1.416–12.471; P = 0.010) analysis.

Conclusions: CTCs affect the outcome of patients with pancreatic cancer independent from other risk factors, including patients receiving (adjuvant) cytotoxic therapy. CTC stratification may allow a better upfront identification of patients with a longer lifespan who might profit from new adjuvant therapies. Clin Cancer Res; 24(12); 2844–50. ©2018 AACR.

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Ensartinib (X-396) in ALK-Positive Non-Small Cell Lung Cancer: Results from a First-in-Human Phase I/II, Multicenter Study

Purpose: Evaluate safety and determine the recommended phase II dose (RP2D) of ensartinib (X-396), a potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), and evaluate preliminary pharmacokinetics and antitumor activity in a first-in-human, phase I/II clinical trial primarily in patients with non–small cell lung cancer (NSCLC).

Patients and Methods: In dose escalation, ensartinib was administered at doses of 25 to 250 mg once daily in patients with advanced solid tumors; in dose expansion, patients with advanced ALK-positive NSCLC were administered 225 mg once daily. Patients who had received prior ALK TKI(s) and patients with brain metastases were eligible.

Results: Thirty-seven patients enrolled in dose escalation, and 60 enrolled in dose expansion. The most common treatment-related toxicities were rash (56%), nausea (36%), pruritus (28%), vomiting (26%), and fatigue (22%); 23% of patients experienced a treatment-related grade 3 to 4 toxicity (primarily rash and pruritus). The maximum tolerated dose was not reached, but the RP2D was chosen as 225 mg based on the frequency of rash observed at 250 mg without improvement in activity. Among the ALK-positive efficacy evaluable patients treated at ≥200 mg, the response rate (RR) was 60%, and median progression-free survival (PFS) was 9.2 months. RR in ALK TKI-naïve patients was 80%, and median PFS was 26.2 months. In patients with prior crizotinib only, the RR was 69% and median PFS was 9.0 months. Responses were also observed in the central nervous system, with an intracranial RR of 64%.

Conclusions: Ensartinib was active and generally well tolerated in patients with ALK-positive NSCLC. Clin Cancer Res; 24(12); 2771–9. ©2018 AACR.

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Tumor-Derived GM-CSF Promotes Granulocyte Immunosuppression in Mesothelioma Patients

Purpose: The cross-talk between tumor cells, myeloid cells, and T cells can play a critical role in tumor pathogenesis and response to immunotherapies. Although the etiology of mesothelioma is well understood, the impact of mesothelioma tumor cells on the surrounding immune microenvironment is less well studied. In this study, the effect of the mesothelioma tumor microenvironment on circulating and infiltrating granulocytes and T cells is investigated.

Experimental Design: Tumor tissues and peripheral blood from mesothelioma patients were evaluated for presence of granulocytes, which were then tested for their T-cell suppression potential. Different cocultures of granulocytes and/or mesothelioma tumor cells and/or T cells were set up to identify the mechanism of T-cell inhibition.

Results: Analysis of human tumors showed that the mesothelioma microenvironment is enriched in infiltrating granulocytes, which inhibit T-cell proliferation and activation. Characterization of the whole blood at diagnosis identified similar, circulating, immunosuppressive CD11b⁺CD15⁺HLADR^– granulocytes at increased frequency compared with healthy controls. Culture of healthy-donor granulocytes with human mesothelioma cells showed that GM-CSF upregulates NOX2 expression and the release of reactive oxygen species (ROS) from granulocytes, resulting in T-cell suppression. Immunohistochemistry and transcriptomic analysis revealed that a majority of mesothelioma tumors express GM-CSF and that higher GM-CSF expression correlated with clinical progression. Blockade of GM-CSF with neutralizing antibody, or ROS inhibition, restored T-cell proliferation, suggesting that targeting of GM-CSF could be of therapeutic benefit in these patients.

Conclusions: Our study presents the mechanism behind the cross-talk between mesothelioma tumors and the immune microenvironment and indicates that targeting GM-CSF could be a novel treatment strategy to augment immunotherapy in patients with mesothelioma. Clin Cancer Res; 24(12); 2859–72. ©2018 AACR.

https://ift.tt/2sXbEAT

A Novel TGF{beta} Trap Blocks Chemotherapeutics-Induced TGF{beta}1 Signaling and Enhances Their Anticancer Activity in Gynecologic Cancers

Purpose: We investigated the mechanisms of how TGFβ pathway is activated by chemotherapeutics and whether a novel TGFβ trap called RER can block chemotherapeutics-induced TGFβ pathway activation and enhance their antitumor activity in gynecologic cancer.

Patients and Methods: An unbiased bioinformatic analysis of differentially expressed genes in 31 ovarian cases due to chemotherapy was used to identify altered master regulators. Phosphorylated Smad2 was determined in 30 paired cervical cancer using IHC. Furthermore, the effects of chemotherapeutics on TGFβ signaling and function, and the effects of RER on chemotherapy-induced TGFβ signaling were determined in gynecologic cancer cells.

Results: Chemotherapy-induced transcriptome alteration in ovarian cancer was significantly associated with TGFβ signaling activation. Chemotherapy was found to activate TGFβ signaling as indicated by phosphorylated Smad2 in paired cervical tumor samples (pre- and post-chemotherapy). Similar to TGFβ1, chemotherapeutics were found to stimulate Smad2/3 phosphorylation, cell migration, and markers related to epithelial–mesenchymal transition (EMT) and cancer stem cells (CSC). These TGFβ-like effects were due to the stimulation of TGFβ1 expression and secretion, and could all be abrogated by TGFβ inhibitors including a novel TGFβ trap protein called RER both in vitro and in vivo. Importantly, combination treatment with RER and cisplatin showed a higher tumor inhibitory activity than either agent alone in a xenograft model of ovarian cancer.

Conclusions: Chemotherapeutics can stimulate TGFβ1 production and consequently enhance TGFβ signaling, EMT, and CSC features resulting in reduced chemo-sensitivity. Combination therapy with a TGFβ inhibitor should alleviate this unintended side effect of chemotherapeutics and enhance their therapeutic efficacy. Clin Cancer Res; 24(12); 2780–93. ©2018 AACR.

https://ift.tt/2sWUfs7

RIP1-HAT1-SIRT Complex Identification and Targeting in Treatment and Prevention of Cancer

Purpose: Alteration in cell death is a hallmark of cancer. A functional role regulating survival, apoptosis, and necroptosis has been attributed to RIP1/3 complexes.

Experimental Design: We have investigated the role of RIP1 and the effects of MC2494 in cell death induction, using different methods as flow cytometry, transcriptome analysis, immunoprecipitation, enzymatic assays, transfections, mutagenesis, and in vivo studies with different mice models.

Results: Here, we show that RIP1 is highly expressed in cancer, and we define a novel RIP1/3–SIRT1/2–HAT1/4 complex. Mass spectrometry identified five acetylations in the kinase and death domain of RIP1. The novel characterized pan-SIRT inhibitor, MC2494, increases RIP1 acetylation at two additional sites in the death domain. Mutagenesis of the acetylated lysine decreases RIP1-dependent cell death, suggesting a role for acetylation of the RIP1 complex in cell death modulation. Accordingly, MC2494 displays tumor-selective potential in vitro, in leukemic blasts ex vivo, and in vivo in both xenograft and allograft cancer models. Mechanistically, MC2494 induces bona fide tumor-restricted acetylated RIP1/caspase-8–mediated apoptosis. Excitingly, MC2494 displays tumor-preventive activity by blocking 7,12-dimethylbenz(α)anthracene–induced mammary gland hyperproliferation in vivo.

Conclusions: These preventive features might prove useful in patients who may benefit from a recurrence-preventive approach with low toxicity during follow-up phases and in cases of established cancer predisposition. Thus, targeting the newly identified RIP1 complex may represent an attractive novel paradigm in cancer treatment and prevention. Clin Cancer Res; 24(12); 2886–900. ©2018 AACR.

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Correction: TEM8/ANTXR1-Specific CAR T Cells as a Targeted Therapy for Triple-Negative Breast Cancer

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Correction: Ubiquitous Release of Exosomal Tumor Suppressor miR-6126 from Ovarian Cancer Cells

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Retraction: Identification of Brain-Derived Neurotrophic Factor as a Novel Functional Protein in Hepatocellular Carcinoma

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Retraction: The Potential Role of Hypoxia Inducible Factor 1{alpha} in Tumor Progression after Hypoxia and Chemotherapy in Hepatocellular Carcinoma

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Retraction: Demethylation-Linked Activation of Urokinase Plasminogen Activator Is Involved in Progression of Prostate Cancer

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Case Studies of Gastric, Lung, and Oral Cancer Connect Etiologic Agent Prevalence to Cancer Incidence

Obtaining detailed individual-level data on both exposure and cancer outcomes is challenging, and it is difficult to understand and characterize how temporal aspects of exposures translate into cancer risk. We show that, in lieu of individual-level information, population-level data on cancer incidence and etiologic agent prevalence can be leveraged to investigate cancer mechanisms and to better characterize and predict cancer trends. We use mechanistic carcinogenesis models [multistage clonal expansion (MSCE) models] and data on smoking, Helicobacter pylori (H. pylori), and HPV infection prevalence to investigate trends of lung, gastric, and HPV-related oropharyngeal cancers. MSCE models are based on the initiation–promotion–malignant conversion paradigm and allow for interpretation of trends in terms of general biological mechanisms. We assumed the rates of initiation depend on the prevalence of the corresponding risk factors. We performed two types of analysis, using the agent prevalence and cancer incidence data to estimate the model parameters and using cancer incidence data to infer the etiologic agent prevalence as well as the model parameters. By including risk factor prevalence, MSCE models with as few as three parameters closely reproduced 40 years of age-specific cancer incidence data. We recovered trends of H. pylori prevalence in the United States and demonstrated that cohort effects can explain the observed bimodal, age-specific pattern of oral HPV prevalence in men. Our results demonstrate the potential for joint analyses of population-level cancer and risk factor data through mechanistic modeling. This approach can be a first step in systematically testing relationships between exposures and cancer risk when individual-level data is lacking.Significance: Analysis of trends in risk-factor prevalence and cancer incidence can shed light on cancer mechanisms and the way that carcinogen exposure through time shapes the risk of cancer at different ages.Graphical Abstract: https://ift.tt/2JNrqVq. Cancer Res; 78(12); 3386–96. ©2018 AACR.

https://ift.tt/2l8M1sA

Retraction: Small Interfering RNA-Directed Reversal of Urokinase Plasminogen Activator Demethylation Inhibits Prostate Tumor Growth and Metastasis

https://ift.tt/2l8ylhc

Zika Virus Selectively Kills Aggressive Human Embryonal CNS Tumor Cells In Vitro and In Vivo

Zika virus (ZIKV) is largely known for causing brain abnormalities due to its ability to infect neural progenitor stem cells during early development. Here, we show that ZIKV is also capable of infecting and destroying stem-like cancer cells from aggressive human embryonal tumors of the central nervous system (CNS). When evaluating the oncolytic properties of Brazilian Zika virus strain (ZIKVBR) against human breast, prostate, colorectal, and embryonal CNS tumor cell lines, we verified a selective infection of CNS tumor cells followed by massive tumor cell death. ZIKVBR was more efficient in destroying embryonal CNS tumorspheres than normal stem cell neurospheres. A single intracerebroventricular injection of ZIKVBR in BALB/c nude mice bearing orthotopic human embryonal CNS tumor xenografts resulted in a significantly longer survival, decreased tumor burden, fewer metastasis, and complete remission in some animals. Tumor cells closely resembling neural stem cells at the molecular level with activated Wnt signaling were more susceptible to the oncolytic effects of ZIKVBR. Furthermore, modulation of Wnt signaling pathway significantly affected ZIKVBR-induced tumor cell death and viral shedding. Altogether, these preclinical findings indicate that ZIKVBR could be an efficient agent to treat aggressive forms of embryonal CNS tumors and could provide mechanistic insights regarding its oncolytic effects.Significance: Brazilian Zika virus strain kills aggressive metastatic forms of human CNS tumors and could be a potential oncolytic agent for cancer therapy. Cancer Res; 78(12); 3363–74. ©2018 AACR.

https://ift.tt/2lcbd1F

MVisAGe Identifies Concordant and Discordant Genomic Alterations of Driver Genes in Squamous Tumors

Integrated analyses of multiple genomic datatypes are now common in cancer profiling studies. Such data present opportunities for numerous computational experiments, yet analytic pipelines are limited. Tools such as the cBioPortal and Regulome Explorer, although useful, are not easy to access programmatically or to implement locally. Here, we introduce the MVisAGe R package, which allows users to quantify gene-level associations between two genomic datatypes to investigate the effect of genomic alterations (e.g., DNA copy number changes on gene expression). Visualizing Pearson/Spearman correlation coefficients according to the genomic positions of the underlying genes provides a powerful yet novel tool for conducting exploratory analyses. We demonstrate its utility by analyzing three publicly available cancer datasets. Our approach highlights canonical oncogenes in chr11q13 that displayed the strongest associations between expression and copy number, including CCND1 and CTTN, genes not identified by copy number analysis in the primary reports. We demonstrate highly concordant usage of shared oncogenes on chr3q, yet strikingly diverse oncogene usage on chr11q as a function of HPV infection status. Regions of chr19 that display remarkable associations between methylation and gene expression were identified, as were previously unreported miRNA–gene expression associations that may contribute to the epithelial-to-mesenchymal transition.Significance: This study presents an important bioinformatics tool that will enable integrated analyses of multiple genomic datatypes. Cancer Res; 78(12); 3375–85. ©2018 AACR.

https://ift.tt/2t79aiR

Rho Kinase Inhibition by AT13148 Blocks Pancreatic Ductal Adenocarcinoma Invasion and Tumor Growth

The high mortality of pancreatic cancer demands that new therapeutic avenues be developed. The orally available small-molecule inhibitor AT13148 potently inhibits ROCK1 and ROCK2 kinases that regulate the actomyosin cytoskeleton. We previously reported that ROCK kinase expression increases with human and mouse pancreatic cancer progression and that conditional ROCK activation accelerates mortality in a genetically modified LSL-KrasG12D; LSL-p53R172H; Pdx1-Cre; (KPC) mouse pancreatic cancer model. In this study, we show that treatment of KPC mouse and human TKCC5 patient-derived pancreatic tumor cells with AT13148, as well as the ROCK-selective inhibitors Y27632 and H1152, act comparably in blocking ROCK substrate phosphorylation. AT13148, Y27632, and H1152 induced morphologic changes and reduced cellular contractile force generation, motility on pliable discontinuous substrates, and three-dimensional collagen matrix invasion. AT13148 treatment reduced subcutaneous tumor growth and blocked invasion of healthy pancreatic tissue by KPC tumor cells in vivo without affecting proliferation, suggesting a role for local tissue invasion as a contributor to primary tumor growth. These results suggest that AT13148 has antitumor properties that may be beneficial in combination therapies or in the adjuvant setting to reduce pancreatic cancer cell invasion and slow primary tumor growth. AT13148 might also have the additional benefit of enabling tumor resection by maintaining separation between tumor and healthy tissue boundaries.Significance: Preclinical evaluation of a small-molecule ROCK inhibitor reveals significant effects on PDAC invasion and tumor growth, further validating ROCK kinases as viable therapeutic targets in pancreatic cancer. Cancer Res; 78(12); 3321–36. ©2018 AACR.

https://ift.tt/2yaqqJC

YAP/TAZ Initiates Gastric Tumorigenesis via Upregulation of MYC

YAP and TAZ play oncogenic roles in various organs, but the role of YAP/TAZ in gastric cancer remains unclear. Here, we show that YAP/TAZ activation initiates gastric tumorigenesis in vivo and verify its significance in human gastric cancer. In mice, YAP/TAZ activation in the pyloric stem cell led to step-wise tumorigenesis. RNA sequencing identified MYC as a decisive target of YAP, which controls MYC at transcriptional and posttranscriptional levels. These mechanisms tightly regulated MYC in homeostatic conditions, but YAP activation altered this balance by impeding miRNA processing, causing a shift towards MYC upregulation. Pharmacologic inhibition of MYC suppressed YAP-dependent phenotypes in vitro and in vivo, verifying its functional role as a key mediator. Human gastric cancer samples also displayed a significant correlation between YAP and MYC. We reanalyzed human transcriptome data to verify enrichment of YAP signatures in a subpopulation of gastric cancers and found that our model closely reflected the molecular pattern of patients with high YAP activity. Overall, these results provide genetic evidence of YAP/TAZ as oncogenic initiators and drivers for gastric tumors with MYC as the key downstream mediator. These findings are also evident in human gastric cancer, emphasizing the significance of YAP/TAZ signaling in gastric carcinogenesis.Significance: YAP/TAZ activation initiates gastric carcinogenesis with MYC as the key downstream mediator. Cancer Res; 78(12); 3306–20. ©2018 AACR.

https://ift.tt/2l95rO3

Adoptive Immunotherapy Using PRAME-Specific T Cells in Medulloblastoma

Medulloblastoma is the most frequent malignant childhood brain tumor with a high morbidity. Identification of new therapeutic targets would be instrumental in improving patient outcomes. We evaluated the expression of the tumor-associated antigen PRAME in biopsies from 60 patients with medulloblastoma. PRAME expression was detectable in 82% of tissues independent of molecular and histopathologic subgroups. High PRAME expression also correlated with worse overall survival. We next investigated the relevance of PRAME as a target for immunotherapy. Medulloblastoma cells were targeted using genetically modified T cells with a PRAME-specific TCR (SLL TCR T cells). SLL TCR T cells efficiently killed medulloblastoma HLA-A*02+ DAOY cells as well as primary HLA-A*02+ medulloblastoma cells. Moreover, SLL TCR T cells controlled tumor growth in an orthotopic mouse model of medulloblastoma. To prevent unexpected T-cell–related toxicity, an inducible caspase-9 (iC9) gene was introduced in frame with the SLL TCR; this safety switch triggered prompt elimination of genetically modified T cells. Altogether, these data indicate that T cells genetically modified with a high-affinity, PRAME-specific TCR and iC9 may represent a promising innovative approach for treating patients with HLA-A*02+ medulloblastoma.Significance: These findings identify PRAME as a medulloblastoma tumor-associated antigen that can be targeted using genetically modified T cells. Cancer Res; 78(12); 3337–49. ©2018 AACR.

https://ift.tt/2l95rh1

CD163 Is Required for Protumoral Activation of Macrophages in Human and Murine Sarcoma

Recent findings have shown the significance of CD163-positive macrophages in tumor progression, yet there have been few studies on the function of CD163 in macrophages. Here, we uncover the role of CD163 in macrophage activation using CD163-deficient mice and human samples. We detected CD163 in 62 undifferentiated pleomorphic sarcoma samples, in which a high percentage of CD163-positive macrophages was associated with decreased overall survival and higher histologic grade. We observed macrophage-induced tumor cell proliferation in cocultures of human monocyte-derived macrophages and leiomyosarcoma (TYLMS-1) and myxofibrosarcoma (NMFH-1) cell lines, which was abrogated by silencing of CD163. Tumor development of sarcoma (MCA205 and LM8) cells in CD163-deficient mice was significantly abrogated in comparison with wild-type (WT) mice. Coculture with WT peritoneal macrophages significantly increased proliferation of MCA205 cells but decreased in the presence of CD163-deficient macrophages. Production of IL6 and CXCL2 in CD163-deficient macrophages was suppressed in comparison with WT macrophages, and overexpression of CD163 in CD163-deficient macrophages induced production of IL6 and CXCL2. Silencing of IL6 but not CXCL2 abrogated macrophage-induced proliferation of MCA205 cells. Taken together, our results show that CD163 is involved in protumoral activation of macrophages and subsequent development and progression of tumors in mice and humans.Significance: Macrophage CD163-mediated induction of IL6 promotes tumor development and progression in murine and human malignant tumors. Cancer Res; 78(12); 3255–66. ©2018 AACR.

https://ift.tt/2leS4fz

IL22RA1/STAT3 Signaling Promotes Stemness and Tumorigenicity in Pancreatic Cancer

Chronic inflammation is a feature of pancreatic cancer, but little is known about how immune cells or immune cell–related signals affect pancreatic cancer stemness and development. Our previous work showed that IL22/IL22RA1 plays a vital role in acute and chronic pancreatitis progression by mediating cross-talk between immune cells and acinar cells or stellate cells, respectively. Here, we find IL22RA1 is highly but heterogeneously expressed in pancreatic cancer cells, with high expression associated with poor prognosis of patients with pancreatic cancer. The IL22RA1hi population from pancreatic cancer harbored higher stemness potential and tumorigenicity. Notably, IL22 promoted pancreatic cancer stemness via IL22RA1/STAT3 signaling, establishing the mechanism of regulation of cancer stemness by microenvironmental factors. Moreover, STAT3 was indispensable for the maintenance of IL22RA1hi cells. Overall, these findings provide a therapeutic strategy for patients with PDAC with high expression of IL22RA1.Significance: IL22RA1/STAT3 signaling enhances stemness and tumorigenicity in pancreatic cancer. Cancer Res; 78(12); 3293–305. ©2018 AACR.

https://ift.tt/2t78Dxn

Blockade of Myeloid-Derived Suppressor Cell Expansion with All-Trans Retinoic Acid Increases the Efficacy of Antiangiogenic Therapy

Intrinsic and adaptive resistance hampers the success of antiangiogenic therapies (AAT), especially in breast cancer where this treatment modality has proven largely ineffective. Therefore, novel strategies to improve the efficacy of AAT are warranted. Solid tumors such as breast cancer are characterized by a high infiltration of myeloid-derived suppressor cells (MDSC), which are key drivers of resistance to AAT. Therefore, we hypothesized that all-trans retinoic acid (ATRA), which induces differentiation of MDSC into mature cells, could improve the therapeutic effect of AAT. ATRA increased the efficacy of anti–VEGFR2 antibodies alone and in combination with chemotherapy in preclinical breast cancer models. ATRA reverted the anti–VEGFR2-induced accumulation of intratumoral MDSC, alleviated hypoxia, and counteracted the disorganization of tumor microvessels. Mechanistic studies indicate that ATRA treatment blocked the AAT-induced expansion of MDSC secreting high levels of vessel-destabilizing S100A8. Thus, concomitant treatment with ATRA holds the potential to improve AAT in breast cancer and possibly other tumor types.Significance: Increasing the therapeutic efficiency of antiangiogenic drugs by reducing resistance-conferring myeloid-derived suppressor cells might improve breast cancer treatment.Graphical Abstract: https://ift.tt/2JEDxrZ. Cancer Res; 78(12); 3220–32. ©2018 AACR.

https://ift.tt/2t78Xfz

ERAP1-Dependent Antigen Cross-Presentation Determines Efficacy of Adoptive T-cell Therapy in Mice

Cytotoxic T lymphocytes can reject established tumors if their target peptide is efficiently presented by MHC class I molecules (pMHC-I) on the surface of cancerous cells. Therapeutic success upon adoptive T-cell transfer (ATT), however, requires additional cross-presentation of the same pMHC-I on noncancerous cells. Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an enzyme that customizes the N-terminus of proteasome-generated peptides so they can be loaded onto MHC-I molecules in the endoplasmic reticulum (ER). We show here that ERAP1 is critically involved in the process of tumor rejection and assumes a dual role by independently operating on both sides. Direct presentation of two MHC-I–restricted epitopes of a cancer-driving transplantation rejection antigen through ERAP1 moderately affected tumor rejection by adoptively transferred T-cell receptor gene–modified T cells in each case. ERAP1 expression by antigen cross-presenting cells of the ATT recipients was critical for expansion of therapeutic monospecific T cells and correlated with tumor rejection. Specifically, lack of ERAP1 expression in the ATT recipient's noncancerous cells enabled progression of pMHC-I–positive, IFNγ-responsive tumors, despite the presence of antigen-specific functional cytotoxic T lymphocytes. These data reveal a decisive role for ERAP1 in T-cell–mediated tumor rejection and will enhance the choice of MHC-I–restricted epitopes targeted by adoptive T-cell transfer.Significance: This study demonstrates a role of ERAP1 in the efficacy of adoptive T-cell transfer and has potential to improve personalized T-cell therapy for solid tumors. Cancer Res; 78(12); 3243–54. ©2018 AACR.

https://ift.tt/2yctcyl

Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction

Mounting clinical and preclinical evidence supports a key role for sustained adrenergic signaling in the tumor microenvironment as a driver of tumor growth and progression. However, the mechanisms by which adrenergic neurotransmitters are delivered to the tumor microenvironment are not well understood. Here we present evidence for a feed-forward loop whereby adrenergic signaling leads to increased tumoral innervation. In response to catecholamines, tumor cells produced brain-derived neurotrophic factor (BDNF) in an ADRB3/cAMP/Epac/JNK-dependent manner. Elevated BDNF levels in the tumor microenvironment increased innervation by signaling through host neurotrophic receptor tyrosine kinase 2 receptors. In patients with cancer, high tumor nerve counts were significantly associated with increased BDNF and norepinephrine levels and decreased overall survival. Collectively, these data describe a novel pathway for tumor innervation, with resultant biological and clinical implications.Significance: Sustained adrenergic signaling promotes tumor growth and metastasis through BDNF-mediated tumoral innervation. Cancer Res; 78(12); 3233–42. ©2018 AACR.

https://ift.tt/2l95cT9

Clinical Trial of Fluid Infusion Rates for Pediatric Diabetic Ketoacidosis

Clinically apparent brain injuries occur in 0.5 to 0.9% of episodes of diabetic ketoacidosis in children; these brain injuries manifest as sudden neurologic decline and are often associated with morbidity and mortality. Among patients without obvious neurologic decline during treatment for diabetic…

https://ift.tt/2ta0dFw

Fluid Composition, Infusion Rate, and Brain Injury in Diabetic Ketoacidosis

Diabetic ketoacidosis constitutes a profound metabolic disturbance of energy homeostasis with a distinct biochemical profile that is characterized by hyperglycemia, ketonemia, metabolic acidosis, and electrolyte abnormalities. It is caused by deficiency of insulin, the hallmark of type 1 diabetes…

https://ift.tt/2sVI0we

Substitute Decision Making in End-of-Life Care

Three days ago, you were called to the intensive care unit (ICU) to examine Ms. Smith, a 70-year-old woman who had presented to the emergency department earlier that day with progressive shortness of breath. Ms. Smith had reported fatigue, progressive dyspnea, and intermittent fevers over the…

https://ift.tt/2t01nnJ

A Framework for a Battlefield Trauma System for Civilians

No abstract available

https://ift.tt/2t6s2i6

Locally optimal detector design in impulsive noise with unknown distribution

This paper designs the locally optimal detector (LOD) in additive white impulsive noise with unknown distribution. Unlike traditional LODs derived from a known or approximated noise probability density functio...

https://ift.tt/2Mrn881

Breast Cancer in Men

Breast cancer in men is a rare and understudied disease. Few prospective studies focusing on breast cancer in men have been conducted, and clinical trials of breast cancer treatments have routinely excluded men. Most of the published data have been collected from small cohorts of patients treated…

https://ift.tt/2JPvBn0

Left Main Coronary Artery Aneurysm

A 49-year-old man with hypertension was referred to our hospital for recurrent angina after receiving recombinant tissue plasminogen activator for acute ST-segment elevation myocardial infarction. His blood pressure was 113/68 mm Hg, and his heart rate was 110 beats per minute. An electrocardiogram…

https://ift.tt/2HNbp04

Randomized trial of iReadMore word reading training and brain stimulation in central alexia

Abstract

Central alexia is an acquired reading disorder co-occurring with a generalized language deficit (aphasia). We tested the impact of a novel training app, 'iReadMore', and anodal transcranial direct current stimulation of the left inferior frontal gyrus, on word reading ability in central alexia. The trial was registered at www.clinicaltrials.gov (NCT02062619). Twenty-one chronic stroke patients with central alexia participated. A baseline-controlled, repeated-measures, crossover design was used. Participants completed two 4-week blocks of iReadMore training, one with anodal stimulation and one with sham stimulation (order counterbalanced between participants). Each block comprised 34 h of iReadMore training and 11 stimulation sessions. Outcome measures were assessed before, between and after the two blocks. The primary outcome measures were reading ability for trained and untrained words. Secondary outcome measures included semantic word matching, sentence reading, text reading and a self-report measure. iReadMore training resulted in an 8.7% improvement in reading accuracy for trained words (95% confidence interval 6.0 to 11.4; Cohen's d = 1.38) but did not generalize to untrained words. Reaction times also improved. Reading accuracy gains were still significant (but reduced) 3 months after training cessation. Anodal transcranial direct current stimulation (compared to sham), delivered concurrently with iReadMore, resulted in a 2.6% (95% confidence interval −0.1 to 5.3; d = 0.41) facilitation for reading accuracy, both for trained and untrained words. iReadMore also improved performance on the semantic word-matching test. There was a non-significant trend towards improved self-reported reading ability. However, no significant changes were seen at the sentence or text reading level. In summary, iReadMore training in post-stroke central alexia improved reading ability for trained words, with good maintenance of the therapy effect. Anodal stimulation resulted in a small facilitation (d = 0.41) of learning and also generalized to untrained items.awy138media15796149281001

https://ift.tt/2JBWlbf

Macroglossia in Light-Chain Amyloidosis

A 78-year-old man presented to the emergency department with a 2-week history of generalized edema, weakness, and chest pain. He reported that during the past year his tongue had become larger and increasingly stiff and that it had become difficult for him to swallow. Physical examination revealed…

https://ift.tt/2HQmhdu

Breast Cancer in Men

Breast cancer in men is a rare and understudied disease. Few prospective studies focusing on breast cancer in men have been conducted, and clinical trials of breast cancer treatments have routinely excluded men. Most of the published data have been collected from small cohorts of patients treated…

https://ift.tt/2JPvBn0

Encouraging Trends in Modern Phase 1 Oncology Trials

To the Editor: Critics have raised a fundamental ethical challenge about phase 1 cancer research. They point to an expected paucity of benefits, since approximately 5% of patients in phase 1 trials are reported to have tumor shrinkage. We conducted a search of the literature using PubMed to…

https://ift.tt/2tajPsT

Infantile Pulmonary Teratoid Tumor

To the Editor: Pulmonary blastoma, an uncommon lung tumor with both epithelial and mesenchymal components, is typically diagnosed in mid-to-late adulthood. Although it is rare in children, it should be distinguished from pleuropulmonary blastoma, a mesenchymal tumor. Pleuropulmonary blastomas and…

https://ift.tt/2JMT7Om

Complete Responses in the TEMPI Syndrome after Treatment with Daratumumab

To the Editor: First described in 2011, the TEMPI syndrome is a rare multisystem disease characterized by telangiectasias, an elevated erythropoietin level and erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and intrapulmonary shunting. Treatment with bortezomib led to partial…

https://ift.tt/2l8wbyh

Dual MAPK inhibition is an effective therapeutic strategy for a subset of class II BRAF mutant melanoma

Purpose: Dual MAPK pathway inhibition (dMAPKi) with BRAF and MEK inhibitors improves survival in BRAF V600E/K mutant melanoma, but the efficacy of dMAPKi in non-V600 BRAF mutant tumors is poorly understood. We sought to characterize the responsiveness of class II (enhanced kinase activity, dimerization dependent) BRAF mutant melanoma to dMAPKi. Experimental Design: Tumors from patients with BRAF WT, V600E (class I) and L597S (class II) metastatic melanoma were used to generate patient-derived-xenografts (PDX). We assembled a panel of melanoma cell lines with class IIa (activation segment) or IIb (p-loop) mutations and compared these to wild-type or V600E/K BRAF mutant cells. Cell lines and PDXs were treated with BRAFi (vemurafenib, dabrafenib, encorafenib, LY3009120), MEKi (cobimetinib, trametinib, binimetinib) or the combination. We identified two patients with BRAF L597S metastatic melanoma who were treated with dMAPKi. Results: BRAFi impaired MAPK signalling and cell growth in class I and II BRAF mutant cells. dMAPKi was more effective than either single MAPKi at inhibiting cell growth in all class II BRAF mutant cells tested. dMAPKi caused tumor regression in two melanoma PDXs with class II BRAF mutations, and prolonged survival of mice with class II BRAF mutant melanoma brain metastases. Two patients with BRAF L597S mutant melanoma clinically responded to dMAPKi. Conclusions: Class II BRAF mutant melanoma are growth inhibited by dMAPKi. Responses to dMAPKi have been observed in two patients with class II BRAF mutant melanoma. This data provides rationale for clinical investigation of dMAPKi in patients with class II BRAF mutant metastatic melanoma.

https://ift.tt/2JBBkxv

Bigger is not always better: Tumor size and prognosis in advanced melanoma

Tumor burden is a key consideration for the treatment of solid malignancies. Large baseline tumor size (an assessment of volume of disease in target lesions prior to treatment), elevated LDH, and site of disease are prognostic of poor overall survival for patients with advanced melanoma treated with pembrolizumab.

https://ift.tt/2LP5NEU

Infantile Pulmonary Teratoid Tumor

To the Editor: Pulmonary blastoma, an uncommon lung tumor with both epithelial and mesenchymal components, is typically diagnosed in mid-to-late adulthood. Although it is rare in children, it should be distinguished from pleuropulmonary blastoma, a mesenchymal tumor. Pleuropulmonary blastomas and…

https://ift.tt/2JMT7Om

The Microbiome and Systemic Lupus Erythematosus

How can it be that such a repugnant substance, feces, is also the key to our well-being? Fecal bacteria are essential to life, and humans are not alone in their dependence on the microbial world. The fruit fly requires acetic acid from Acetobacter pomorum. The bobtail squid needs the luminescence…

https://ift.tt/2sYMzWg

Adipocyte-derived lipids mediate melanoma progression via FATP proteins [Research Articles]

Advanced, metastatic melanomas frequently grow in subcutaneous tissues and portend a poor prognosis. Though subcutaneous tissues are largely composed of adipocytes, the mechanisms by which adipocytes influence melanoma are poorly understood. Using in vitro and in vivo models, we find that adipocytes increase proliferation and invasion of adjacent melanoma cells. Additionally, adipocytes directly transfer lipids to melanoma cells, which alters tumor cell metabolism. Adipocyte-derived lipids are transferred to melanoma cells through the FATP/SLC27A family of lipid transporters expressed on the tumor cell surface. Among the six FATP/SLC27A family members, melanomas significantly overexpress FATP1/SLC27A1. Melanocyte-specific FATP1 expression cooperates with BRAFV600E in transgenic zebrafish to accelerate melanoma development, an effect that is similarly seen in mouse xenograft studies. Pharmacologic blockade of FATPs with the small molecule Lipofermata abrogates lipid transport into melanoma cells and reduces melanoma growth and invasion. These data demonstrate that stromal adipocytes can drive melanoma progression through FATP lipid transporters, and represents a new target aimed at interrupting adipocyte-melanoma cross-talk.

https://ift.tt/2MtkfDS

Breast Cancer in Men

Breast cancer in men is a rare and understudied disease. Few prospective studies focusing on breast cancer in men have been conducted, and clinical trials of breast cancer treatments have routinely excluded men. Most of the published data have been collected from small cohorts of patients treated…

https://ift.tt/2JPvBn0

Macroglossia in Light-Chain Amyloidosis

A 78-year-old man presented to the emergency department with a 2-week history of generalized edema, weakness, and chest pain. He reported that during the past year his tongue had become larger and increasingly stiff and that it had become difficult for him to swallow. Physical examination revealed…

https://ift.tt/2HQmhdu

Substitute Decision Making in End-of-Life Care

Three days ago, you were called to the intensive care unit (ICU) to examine Ms. Smith, a 70-year-old woman who had presented to the emergency department earlier that day with progressive shortness of breath. Ms. Smith had reported fatigue, progressive dyspnea, and intermittent fevers over the…

https://ift.tt/2t01nnJ

Recognizing Blind Spots — A Remedy for Gender Bias in Medicine?

As the senior resident in an intensive care unit (ICU), I had just finished a particularly difficult discussion with a patient's family. My patient was an elderly man with advanced dementia and a weak heart who had collapsed at home. Now that he was ventilator-dependent and showing no signs of…

https://ift.tt/2sYpS4J

Case 18-2018: A 45-Year-Old Woman with Hypertension, Fatigue, and Altered Mental Status

Presentation of Case. Dr. Sally A. Ingham (Medicine): A 45-year-old woman was admitted to this hospital because of dyspnea on exertion, fatigue, and confusion. The patient had been in her usual state of health until 18 months before the current admission, when the blood pressure was noted to be…

https://ift.tt/2JLbnaQ

Dry Eye

Dry eye is a common disorder of the ocular surface that affects millions of people worldwide, with varying severity. At a minimum, dry eye causes discomfort, but it can also cause disabling pain and fluctuating vision, substantially affecting vision-related quality of life by limiting such…

https://ift.tt/2HNbtNm

Lymphangioleiomyomatosis

A 44-year-old woman presented to the emergency department with acute chest pain after several months of progressive dyspnea. Her oxygen saturation was 92% while she was breathing ambient air, and the physical examination was notable for diminished breath sounds on the right side. Computed…

https://ift.tt/2JDZ4Bc

Left Main Coronary Artery Aneurysm

A 49-year-old man with hypertension was referred to our hospital for recurrent angina after receiving recombinant tissue plasminogen activator for acute ST-segment elevation myocardial infarction. His blood pressure was 113/68 mm Hg, and his heart rate was 110 beats per minute. An electrocardiogram…

https://ift.tt/2HNbp04

A Shocking Turn of Events

In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information by sharing relevant background and reasoning with the reader (regular type). The authors' commentary follows. A 38-year-old woman presented to her…

https://ift.tt/2sVGU3y

Substitute Decision Making in End-of-Life Care

Three days ago, you were called to the intensive care unit (ICU) to examine Ms. Smith, a 70-year-old woman who had presented to the emergency department earlier that day with progressive shortness of breath. Ms. Smith had reported fatigue, progressive dyspnea, and intermittent fevers over the…

https://ift.tt/2t01nnJ

Improved Titers against Influenza Drift Variants with a Nanoparticle Vaccine

To the Editor: Paules et al. recently advocated for the development of influenza vaccines "that will protect against seasonal influenza drift variants" and "not be subject to the limitations of egg-based vaccine technology." Improving vaccine responses against A(H3N2) viruses has been a challenge…

https://ift.tt/2JDXD5M

The Scarlet Virus

She was a large woman with an easy grin and open demeanor; her threadbare jacket was often askew but always meticulously clean. It was easy to envision her on the front stoops of Baltimore row houses, chatting with neighbors as they numbed their sorrows with hits of speedball, shots in paper bags.…

https://ift.tt/2yeGFpe

E-Cigarette Flavorings May Impair Vascular Function

THURSDAY, June 14, 2018 -- Flavoring additives used in electronic cigarettes (e-cigarettes) may have adverse effects on blood vessels, according to a study published online June 14 in Arteriosclerosis, Thrombosis, and Vascular Biology. Jessica L....

https://ift.tt/2yc4P3w

Foods With Fat and Carbohydrate Are More Highly Valued

THURSDAY, June 14, 2018 -- Foods containing fat and carbohydrate are more highly valued than those with only fat or carbohydrate, and this potentiated reward is associated with response in brain areas critical for reward valuation, according to a...

https://ift.tt/2MmwO3L

AMA: Federal Government Must Tackle Rising Insulin Prices

THURSDAY, June 14, 2018 -- U.S. officials need to take action to control spiking insulin prices, the American Medical Association (AMA) says. The Federal Trade Commission and the Justice Department should monitor insulin pricing and market...

https://ift.tt/2y9g7FT

AMA President Calls Physicians to Lead in Addressing Gun Violence

THURSDAY, June 14, 2018 -- The issue of gun violence must be addressed by the physician leadership scientifically, in an evidence-based manner, according to remarks issued by the president of the American Medical Association (AMA) at the...

https://ift.tt/2JGu03u

A Pragmatic Trial of E-Cigarettes, Incentives, and Drugs for Smoking Cessation

Most large U.S. companies offer smoking-cessation programs for their employees, and nearly half of those companies offer financial incentives for employees who successfully stop smoking. These benefit designs are motivated by evidence that smoking remains the leading cause of preventable illness…

https://ift.tt/2KMt8GY

Integrating Medical and Nonmedical Services — The Promise and Pitfalls of the CHRONIC Care Act

Efforts to provide more integrated care for Medicare beneficiaries to better address health and well-being needs that are not strictly medical have received a major boost with the enactment of the Creating High-Quality Results and Outcomes Necessary to Improve Chronic (CHRONIC) Care Act as part of…

https://ift.tt/2JFWDOo

Clinical Trial Participants’ Views of the Risks and Benefits of Data Sharing

We are rapidly moving toward a world in which broad sharing of participant-level clinical trial data is the norm. The European Medicines Agency has implemented a policy to expand public access to data concerning products it approves, the Food and Drug Administration is considering how to expand…

https://ift.tt/2LSx7SJ

Assessing Drug Safety in Children — The Role of Real-World Data

Over the past 20 years, several legislative initiatives in the United States have resulted in hundreds of clinical trials assessing the treatment effects of various drugs in children. Since 1998, a total of 712 drug labels have been updated with information from randomized trials about drug use,…

https://ift.tt/2JDUUt4

Knowledge, attitudes and skills in melanoma diagnosis among doctors: a cross sectional study from Sri Lanka

This study aimed to assess the knowledge, attitudes and skills of non-specialist doctors on timely referral of suspicious lesions for melanoma diagnosis.

https://ift.tt/2lapdIX

Hereditary hearing loss SNP-microarray pilot study

Despite recent advancements in diagnostic tools, the genomic landscape of hereditary hearing loss remains largely uncharacterized. One strategy to understand genome-wide aberrations includes the analysis of co...

https://ift.tt/2t9xGQd

The association between the lipid profile and fasting blood glucose with weight related outcomes in healthy obese adults

The present study was conducted on healthy obese persons to determine: (i) the association between total cholesterol, triglycerides, HDL cholesterol, total cholesterol/HDL ratio and fasting blood glucose (FBG)...

https://ift.tt/2levJ1H

Topolnogical classifier for detecting the emergence of epileptic seizures

An innovative method based on topological data analysis is introduced for classifying EEG recordings of patients affected by epilepsy. We construct a topological space from a collection of EEGs signals using P...

https://ift.tt/2ta5tJ8

The impact of bariatric surgery on the resolution of obstructive sleep apnoea

Obesity is associated with a high incidence of obstructive sleep apnoea (OSA). Bariatric surgery is postulated to lead to OSA resolution, but there is inconclusive evidence on its efficacy. We used objective m...

https://ift.tt/2l7ZZLw

Diagnosing Neuropathy in an Obese Patient

We read with interest the recent article by Callaghan et al. (2018), "Better diagnostic accuracy of neuropathy in obesity: A new challenge for neurologists." This is a commonly encountered problem, and the authors are commended for comparing a variety of diagnostic tools for three common types of peripheral neuropathy.

https://ift.tt/2tdPx90

Central Neuropathic Pain in Paraplegia Alters Movement Related Potentials

Central Neuropathic Pain (CNP) is caused by an injury to the somatosensory system (Jensen et al. 2011) affecting more than 40% Spinal Cord Injured (SCI) patients (Siddall 2003).1 The cortical activity of SCI patients is thus affected by both CNP and paralysis (Boord et al. 2008, Vuckovic et al. 2014). To understand the effect of SCI on EEG during motor tasks, researchers have analysed both event-related synchronisation/desynchronisation (ERS/ERD) (Pfurtscheller et al. 2009) and movement related cortical potential (MRCP) (Castro et al.

https://ift.tt/2lalZp5

Altered Electrophysiological Correlates of Motor Inhibition and Performance Monitoring in Tourette’s Syndrome

Tourette's syndrome (TS) is a childhood onset neurodevelopmental disorder characterized by the presence of motor and vocal tics. Tics fluctuate in frequency and intensity; they are sensitive to context and often amplified in exaggerated emotional states. Tics are often preceded by a stressful sensation, the premonitory urge (Leckman et al. 1993). Comorbid disorders are common in TS and prominently include obsessive-compulsive disorder (OCD), attention-deficit hyperactivity disorder (ADHD) and affective disorders (Robertson 2006; Simpson et al.

https://ift.tt/2ydt15z

Reply to “Diagnosing Neuropathy in an Obese Patient”: Measuring neuropathy in obese populations: Nerve conduction studies

We appreciate the comments by Drs. Bodofsky and Carter (Bodofsky and Carter, 2018) pertaining to our article "Better diagnostic accuracy of neuropathy in obesity: A new challenge for neurologists" (Callaghan et al., 2018). We agree that the diagnostic characteristics of the Utah Early Neuropathy Score (UENS) and the Michigan Neuropathy Screening Instrument (MNSI) examination scores may be overestimated secondary to incorporation bias as pointed out in our limitations section. We also agree that the confidence intervals of our AUC estimates do not allow definitive comparisons for all of the neuropathy measures tested.

https://ift.tt/2l9yhxL

Transcranial magnetic stimulation in hereditary ataxias: diagnostic utility, pathophysiological insight and treatment

Transcranial magnetic stimulation (TMS) is a non-invasive method for stimulation and modulation of the human brain allowing the study of corticospinal tract function, facilitation and inhibition in neural networks and brain plasticity (Wassermann et al., 2008). TMS is based on the fundamental principles of electromagnetic induction: a brief current in the stimulating coil induces a magnetic field that in turn induces an electric current in brain regions underneath the stimulating coil. In motor cortex, this leads to action potentials in corticospinal cells and multiple descending corticospinal volleys that synapse in spinal gray matter onto alpha-motoneurons, causing in turn action potentials and, finally, activation of muscles which can be recorded as motor evoked potentials (MEPs) by surface electromyography (Hallett, 2007; Kobayashi and Pascual-Leone, 2003) (Fig.

https://ift.tt/2y9603T

How we resect colorectal polyps <20 mm in size

We review our approach to resection of colorectal polyps <20 mm in size. Careful inspection of all lesions is appropriate to assess the type of lesion (adenoma vs serrated) and evaluate the risk of cancer, which is highly associated with lesion size. Polyp resection is in the midst of a "cold revolution," particularly for lesions <10 mm in size, but also for some larger lesions. Cold forceps are sometimes appropriate for 1- to 2-mm lesions that can be engulfed in one bite, but we use cold snaring for almost the entire set of lesions <10 mm.

https://ift.tt/2JMsWaB

Tu1032 RISK OF SERIOUS ADVERSE REACTIONS IN ANESTHESIA-ASSISTED COMPLEX LUMINAL ENDOSCOPY PROCEDURES DONE WITHOUT A REGISTERED NURSE, IN AN OUTPATIENT ENDOSCOPY UNIT: EVALUATING MINIMAL STAFFING IN GI ENDOSCOPY

Registered nurses (RNs) play a key role during moderate sedation cases by administering drugs and monitoring patients. However, propofol-based sedation administered by anesthesia is being increasingly used in outpatient (OP) endoscopy units. The Society of Gastroenterology Nurses and Associates (SGNA) released their recommendations in 2012, which requires the presence of at least one RN regardless of anesthesia assistance during a case. However, according to the American Society of Gastrointestinal Endoscopy (ASGE) practice guidelines, presence of an RN is not mandatory during a case when anesthesia is providing the sedation.

https://ift.tt/2sWAFMz

Novel CT-based objective imaging biomarkers of long term radiation-induced lung damage

and Purpose: Recent improvements in lung cancer survival have spurred an interest in understanding and minimizing long term radiation-induced lung damage (RILD). However, there is still no objective criteria to quantify RILD leading to variable reporting across centres and trials. We propose a set of objective imaging biomarkers to quantify common radiological findings observed 12-months after lung cancer radiotherapy (RT).

https://ift.tt/2JPdXzM

Optimizing the Role of Surgery and Radiotherapy in Urethral Cancer Based on Histology and Disease Extent

Optimal management of urethral carcinoma is unknown. A national hospital-based registry was used to evaluate the association of varying local therapies (surgery, radiotherapy, or surgery and radiotherapy) with survival. Overall, surgery and radiotherapy was associated with improved outcomes in locally advanced patients, but subset by histology revealed that adenocarcinoma and transitional cell carcinoma patients experienced improved survival in association with radiotherapy (either definitively or in addition to surgery), while squamous cell carcinoma patients experienced similar survival with surgery and/or radiotherapy.

https://ift.tt/2LRLgzs

Specialist palliative care service for children with life-threatening conditions: A nationwide survey of availability and utilization

According to the International Observatory on End of Life Care, the level of pediatric palliative care in Japan is Level 2 (capacity building) and the current status of palliative care for children in Japan has not been clarified.

https://ift.tt/2sTcvmn

Response to the letter from Goldstein and Sartor

https://ift.tt/2ycj5cD

CKD and Sedentary Time: Results From the Canadian Health Measures Survey

Sedentary behavior and low physical activity are associated with incident diabetes, cardiovascular disease, and early mortality. Previous studies have examined associations between chronic kidney disease (CKD) and physical activity, but little is known about the role of sedentary time.

https://ift.tt/2JBZcB8

Association of Smoking Status With Mortality and Hospitalization in Hemodialysis Patients

The relationship between tobacco smoking and comorbid condition outcomes in hemodialysis (HD) patients is not well understood. This study examined the association of tobacco smoking status with hospitalization and mortality in HD patients.

https://ift.tt/2yb4gqP

Maternal Perceived Stress during Pregnancy Increases Risk for Low Neonatal Iron at Delivery and Depletion of Storage Iron at One Year

To investigate the impact of maternal stress during pregnancy on newborn iron and stage 1 iron deficiency at 1 year of age.

https://ift.tt/2t6hijD

Emergency Department Use of Neuroimaging in Children and Adolescents Presenting with Headache

To evaluate emergency department use and outcomes of neuroimaging for headache in a free-standing children's hospital system.

https://ift.tt/2l7KLGm

Immune-evasive gene switch enables regulated delivery of chondroitinase after spinal cord injury

Abstract

Chondroitinase ABC is a promising preclinical therapy that promotes functional neuroplasticity after CNS injury by degrading extracellular matrix inhibitors. Efficient delivery of chondroitinase ABC to the injured mammalian spinal cord can be achieved by viral vector transgene delivery. This approach dramatically modulates injury pathology and restores sensorimotor functions. However, clinical development of this therapy is limited by a lack of ability to exert control over chondroitinase gene expression. Prior experimental gene regulation platforms are likely to be incompatible with the non-resolving adaptive immune response known to occur following spinal cord injury. Therefore, here we apply a novel immune-evasive dual vector system, in which the chondroitinase gene is under a doxycycline inducible regulatory switch, utilizing a chimeric transactivator designed to evade T cell recognition. Using this novel vector system, we demonstrate tight temporal control of chondroitinase ABC gene expression, effectively removing treatment upon removal of doxycycline. This enables a comparison of short and long-term gene therapy paradigms in the treatment of clinically-relevant cervical level contusion injuries in adult rats. We reveal that transient treatment (2.5 weeks) is sufficient to promote improvement in sensory axon conduction and ladder walking performance. However, in tasks requiring skilled reaching and grasping, only long term treatment (8 weeks) leads to significantly improved function, with rats able to accurately grasp and retrieve sugar pellets. The late emergence of skilled hand function indicates enhanced neuroplasticity and connectivity and correlates with increased density of vGlut1+ innervation in spinal cord grey matter, particularly in lamina III–IV above and below the injury. Thus, our novel gene therapy system provides an experimental tool to study temporal effects of extracellular matrix digestion as well as an encouraging step towards generating a safer chondroitinase gene therapy strategy, longer term administration of which increases neuroplasticity and recovery of descending motor control. This preclinical study could have a significant impact for tetraplegic individuals, for whom recovery of hand function is an important determinant of independence, and supports the ongoing development of chondroitinase gene therapy towards clinical application for the treatment of spinal cord injury.

https://ift.tt/2JVm6CK

Placebo by proxy expectations toward acupuncture change over time: a survey comparing parental expectations to acupuncture pre- and postoperatively

Patients entering a treatment have expectancy to outcome based on their previous experience, the information received, and the credibility of the treatment. Once the treatment has started, patients may detect ...

https://ift.tt/2HNjl1q

Generation of Knock-out Primary and Expanded Human NK Cells Using Cas9 Ribonucleoproteins

Here, we present a protocol to genetically modify primary or expanded human natural killer (NK) cells using Cas9 Ribonucleoproteins (Cas9/RNPs). By using this protocol, we generated human NK cells deficient for transforming growth factor–b receptor 2 (TGFBR2) and hypoxanthine phosphoribosyltransferase 1 (HPRT1).

https://ift.tt/2JBgAG1

Long-term In Vivo Tracking of Inflammatory Cell Dynamics Within Drosophila Pupae

Here we present a protocol for live-imaging wound repair and the associated inflammatory response at high spatio-temporal resolution in vivo. This method utilizes the pupal stage of Drosophila development to enable long-term imaging and tracking of specific cell populations over time and is compatible with efficient RNAi-mediated gene inactivation.

https://ift.tt/2JMbGSO

Optimization of Laser-Capture Microdissection for the Isolation of Enteric Ganglia from Fresh-Frozen Human Tissue

The goal of this protocol is to obtain high-integrity RNA samples from enteric ganglia isolated from unfixed, freshly-resected human intestinal tissue using laser capture microdissection (LCM). This protocol involves preparing flash-frozen samples of human intestinal tissue, cryosectioning, ethanolic staining and dehydration, LCM, and RNA extraction.

https://ift.tt/2MrRl78

Validation of the educational effectiveness of a mobile learning app to improve knowledge about MR image quality optimisation and artefact reduction

Abstract

Aim

The aim was to design an app-based eLearning tool to provide radiographers with information about the physical basis of MR artefacts and practical elimination or/and minimisation strategies to optimise image quality, and to evaluate the impact of a smartphone app on radiographers' knowledge.

Methods

The study used the comparison-experimental approach (pre- and post-test). Thirty-five MR radiographers independently reviewed a prepared series of MR images (n = 25). The participants were requested to identify image quality related errors, to specify error-correction strategies and to score how confident they were in their responses. Participants were then divided into experimental (n = 19) and control cohorts (n = 16). The app was provided to the experimental cohort for 3 months; after this period both cohorts re-reviewed the MR image datasets and repeated their identification of image quality errors.

Results

The results showed a statistically significant difference between control and experimental cohorts relative to participants' pre- to post-test knowledge level. For the experimental cohort, years of experience, qualification and type of hospital were not associated with radiographer knowledge level and confidence in recognising the presence of an image quality error, naming the error and specifying appropriate correction strategies (p > 0.05).

Conclusion

The study identified the potential of the smartphone app as an effective educational tool to support MR radiographers' knowledge in recognising and characterising MR image quality errors.

Key Points

• A high level of knowledge to optimise MR image quality is crucial.

• Ongoing education in image quality optimisation is required.

• The potential role of app as an effective educational tool is identified.

https://ift.tt/2sWcG0c

CDC: U.S. Suicide Rate Rose 30 Percent From 2000 to 2016

THURSDAY, June 14, 2018 -- From 2000 to 2016 there was a 30 percent increase in the age-adjusted suicide rate in the United States, according to a June data brief published by the U.S. Centers for Disease Control and Prevention's National Center for...

https://ift.tt/2ylqcQj

Antipsychotic Tx Linked to Adiposity Changes in Youths

THURSDAY, June 14, 2018 -- Youth receiving antipsychotic treatment have adverse changes in adiposity and insulin sensitivity, with the greatest fat increases seen with olanzapine, according to a study published online June 13 in JAMA...

https://ift.tt/2JRIbSN

Little Evidence Nicotine Preloading Helps Smokers Quit

THURSDAY, June 14, 2018 -- Nicotine preloading does not significantly increase subsequent smoking abstinence in adult daily smokers with tobacco dependence, according to a study published online June 13 in The BMJ. Paul Aveyard, Ph.D., from the...

https://ift.tt/2LPDczd

Illicit Opioid Trade Up With Restrictions on Hydrocodone

THURSDAY, June 14, 2018 -- The U.S. Drug Enforcement Administration's 2014 ruling to reschedule hydrocodone combination products coincided with an increase in illicit trading of opioids through online illicit markets (cryptomarkets), according to a...

https://ift.tt/2JT1Bqo

T2DM Risk in Offspring Greater With T2DM Versus GDM Exposure

THURSDAY, June 14, 2018 -- In utero exposure to type 2 diabetes is associated with increased risk of type 2 diabetes in offspring versus exposure to gestational diabetes, according to a study published online June 11 in JAMA Pediatrics. Brandy A....

https://ift.tt/2LSud07

African-Americans Less Likely to Get Recommended Statin Therapy

THURSDAY, June 14, 2018 -- African-Americans are less likely than whites to be treated with statins or to receive a statin at guideline-recommended intensity, according to a study published online June 13 in JAMA Cardiology. Michael G. Nanna, M.D.,...

https://ift.tt/2JRI9dD

Acute Insomnia Found to Be Common Among Good Sleepers

THURSDAY, June 14, 2018 -- Acute insomnia (AI) is common among good sleepers, and about three-quarters of those with AI recover good sleep, according to a study presented at the annual meeting of the Associated Professional Sleep Societies (SLEEP...

https://ift.tt/2HNalta

Peri-Op RBC Transfusions Linked to Postoperative VTE

THURSDAY, June 14, 2018 -- Perioperative red blood cell (RBC) transfusions are associated with the development of new or progressive postoperative venous thromboembolism (VTE), according to a study published online June 13 in JAMA Surgery. Ruchika...

https://ift.tt/2JT1xHa

Personalized Goals, Cash Motivate Heart Patients to Exercise

THURSDAY, June 14, 2018 -- Personalized goals, combined with financial incentives, motivate heart patients to increase their exercise, according to a study published online June 13 in the Journal of the American Heart Association. Neel P. Chokshi,...

https://ift.tt/2HOdqJj

Fluconazole Use Doesn't Up Risk of Stillbirth, Neonatal Death

THURSDAY, June 14, 2018 -- Fluconazole use in pregnancy seems not to be associated with significantly increased risks of stillbirth or neonatal death, according to a research letter published in the June 12 issue of the Journal of the American...

https://ift.tt/2JT1ues

Mitogen-activated protein kinase eight polymorphisms are associated with immune responsiveness to HBV vaccinations in infants of HBsAg(+)/HBeAg(−) mothers

Infants born to hepatitis B surface antigen (HBsAg) positive mothers are at a higher risk for Hepatitis B virus (HBV) infection. Host genetic background plays an important role in determining the strength of i...

https://ift.tt/2JEyiso

Transmission of rabies through solid organ transplantation: a notable problem in China

Due to the increasing number of DCD transplantations since 2015, the transmission of rabies through solid organ transplantation has become a notable problem in China and has attracted the attention of the public.

https://ift.tt/2HPCmA2

Sero-prevalence and spatial distribution of Rift Valley fever infection among agro-pastoral and pastoral communities during Interepidemic period in the Serengeti ecosystem, northern Tanzania

In the past two decades, Rift Valley Fever (RVF) outbreaks have been reported twice in Tanzania, with the most recent outbreak occurring in 2006/07. Given the ecology and climatic factors that support mosquito...

https://ift.tt/2JCJkhB

Delayed and highly specific antibody response to nonstructural protein 1 (NS1) revealed during natural human ZIKV infection by NS1-based capture ELISA

Zika virus (ZIKV) had spread rapidly in the past few years in southern hemisphere where dengue virus (DENV) had caused epidemic problems for over half a century. The high degree of cross-reactivity of Envelope...

https://ift.tt/2LQu6lW

Trial Produces Practice-Changing Findings for Some Children, Young Adults with Leukemia

This NCI-funded Children's Oncology Group trial tested the addition of nelarabine (Arranon) to standard treatment for children and young adults with T-cell acute lymphoblastic leukemia (T-ALL).

https://ift.tt/2JXFm2N

Development and Validation of an Ultrasensitive Single Molecule Array Digital Enzyme-linked Immunosorbent Assay for Human Interferon-α

Here we present a protocol to describe the development and validation of a single molecule array digital ELISA assay, which enables the ultra-sensitive detection of all IFN-α subtypes in human samples.

https://ift.tt/2sY0yvB

High-sensitivity Detection of Micrometastases Generated by GFP Lentivirus-transduced Organoids Cultured from a Patient-derived Colon Tumor

To allow highly sensitive detection of the disseminating human colorectal cancer (CRC) cells colonizing tissues, we herein show a protocol for efficient transduction of green fluorescent protein (GFP) lentiviral particles into PDX-derived CRC organoid cells prior to their injection into recipient mice, with stereo-fluorescence microscopic observation.

https://ift.tt/2t9tPTk

Effect of a cognitive task on online adjustments when avoiding stepping on an obstacle and stepping on a target during walking in young adults

Abstract

During locomotion, we respond to environmental and task changes by adjusting steps length and width. Different protocols involving stepping on targets and obstacle avoidance suggest the involvement of cortical and subcortical pathways in these online adjustments. The addition of a concomitant cognitive task (CT) can affect these online corrections depending on the neural pathway used. Thereby, we investigated the online adjustment using a target stepping task and a planar obstacle avoidance task in young adults and analyzed the effect of a CT on these adjustments. Twenty young adults executed two blocks of trials of walking performing the target task (TT) and obstacle avoidance task (OAT), with and without a concomitant CT. In the TT, participants stepped on a target projected on the ground, whereas in the OAT they avoided stepping on an obstacle projected on the ground. The target/obstacle could change its original position in four directions at contralateral foot contact on the ground. Overall, the CT did not affect the latency to start the adjustments due to target/obstacle change. The main changes were restricted to the frontal plane adjustments. The latency for the medial and lateral choices in the OAT was ~ 200 ms, whereas for the TT was ~ 150 ms. These results suggest the involvement of a slow cortical pathway in the OAT in the frontal plane modifications. In turn, the TT may be controlled by one of two fast adjustment neural pathways.

https://ift.tt/2t4AUo4

PET Imaging of Neuroinflammation Using [11C]DPA-713 in a Mouse Model of Ischemic Stroke

Positron Emission Tomography (PET) imaging of translocator protein 18 kDa (TSPO) provides a non-invasive means to visualize the dynamic role of neuroinflammation in the development and progression of brain diseases. This protocol describes TSPO-PET and ex vivo autoradiography to detect neuroinflammation in a mouse model of ischemic stroke.

https://ift.tt/2JSfDbK

Analyzing the Photo-oxidation of 2-propanol at Indoor Air Level Concentrations Using Field Asymmetric Ion Mobility Spectrometry

A protocol for determining the effectiveness of photocatalysts in degrading indoor air concentration (ppb) model volatile organic carbons such as 2-propanol is described.

https://ift.tt/2HO4IuE

Comparing appropriateness of antibiotics for nursing home residents by setting of prescription initiation: a cross-sectional analysis

The pervasive, often inappropriate, use of antibiotics in healthcare settings has been identified as a major public health threat due to the resultant widespread emergence of antibiotic resistant bacteria. In ...

https://ift.tt/2lbSzaa

Hepatitis C virus infection and hospital-related outcomes: a systematic review protocol

Introduction

People living with hepatitis C virus (HCV) infection are disproportionately over-represented in the healthcare system due to various individual and contextual circumstances, including comorbidities and socioeconomic marginalisation. With growing trends in morbidity and mortality related to HCV infection, HCV is becoming a significant health and financial burden on the healthcare system, particularly in acute hospital settings. It is noteworthy that with the advent of direct-acting antiviral therapy the increasing number of patients who are cured of HCV could potentially result in different patterns of hospital-related outcomes over time.

Methods and analysis

We will conduct a systematic review of published literature to retrieve quantitative research articles pertaining to hospital outcomes among patients living with HCV. Primary outcomes include hospitalisation rates, length of stay, leaving against medical advice, readmission and in-hospital mortality. In total, five databases will be searched (MEDLINE, EMBASE, CINAHL, PsycINFO and Web of Science). Titles, abstracts and full texts will be independently reviewed by two investigators in three separate stages. The methodological quality of included quantitative research studies will be assessed using a validated tool. Data from included articles will be extracted using a standardised form and synthesised in a narrative account.

Ethics and dissemination

Results of this systematic review could provide a better understanding on how to optimise health systems and services to improve patient outcomes and care. The results of this study may provide future research with a foundation to guide decision-making and for designing and implementing systems-level interventions to improve treatment and care delivery for people living with HCV. Ethical approval for this study was received by the University of British Columbia/Providence Health Care Research Ethics Board. Findings from this study will be disseminated through peer-reviewed publications, presentations, reports and community forums

PROSPERO registration number

CRD42017081082; Pre-results.

https://ift.tt/2sZy0lm

Prevalence and clustering of cardiovascular risk factors: a cross-sectional survey among Nanjing adults in China

Objectives

To estimate prevalence and clustering of cardiovascular risk factors (CRFs), and investigate the association between relevant characteristics and CRF clustering among adults in eastern China.

Design

Community-based cross-sectional study.

Setting

Data were collected by interview survey, physical measurements and laboratory examinations from the 2011 Nanjing Chronic Disease and Risk Factor Surveillance.

Participants

A representative sample of 41 072 residents aged ≥18 years volunteered to participate in the survey, with a response rate of 91.3%. We excluded 1232 subjects due to missing data or having a history of cardiovascular diseases; a total of 39 840 participants were included in the analysis.

Outcome measures

Prevalence and clustering of five major CRFs including hypertension, diabetes, dyslipidaemia, overweight or obesity and current smoking.

Results

Of 39 840 participants (mean age 47.9±16.2 years), 17 964 (45.1%) were men and 21 876 (54.9%) were women. The weighted prevalence of CRFs ranged between 6.2% for diabetes and 35.6% for overweight or obesity. The proportion of CRFs tended to be higher in men, the elderly, participants who lost a life partner, or lived in rural areas, or had lower level of education and total annual income. Overall, 30.1% and 35.2% of participants had one and at least two CRFs, respectively. Multivariate logistic regression revealed that men, older age, loss of a life partner, lower level of socioeconomic status, rural areas, insufficient physical activity or unhealthy diets were positively associated with CVD risk factor clustering, compared with their counterparts.

Conclusions

High regional prevalence of hypertension, dyslipidaemia, overweight or obesity and their clustering are present in Nanjing. The Nanjing government should develop effective public health policies at the regional level especially for high-risk groups, such as enhancing the public's health awareness, organising health promotion programmes, implementing smoke-free law, producing healthy nutrient foods, providing free or low-cost public sports and fitness facilities.

https://ift.tt/2t8ETAb

Effectiveness and safety of golimumab in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis under real-life clinical conditions: non-interventional GO-NICE study in Germany

Objective

The Non Interventional Evaluation with Golumimab (GO-NICE) study aimed to document patient and treatment characteristics as well as clinical effectiveness and safety in adult patients newly treated with the tumour necrosis factor inhibitor golimumab (GLM).

Design

Prospective non-interventional study with 24-month observation per patient.

Setting

158 office-based and clinical-based physicians in Germany.

Intervention

GLM administered in the 50 mg dose subcutaneously in monthly intervals under real-life conditions.

Results

Of the 1613 included patients, 1458 patients were eligible for final analysis: 474 patients with rheumatoid arthritis (RA, 54.9±13.4 years, 72.8% women, 64.7% biologic-naïve), 501 with psoriatic arthritis (PsA, 50.5±12.1 years, 54.1% women, 56.5% biologic-naïve) and 483 with ankylosing spondylitis (AS, 43.6±12.3 years, 66.5% men, 61.0% biologic-naïve). 664 patients completed follow-up (2-year retention rate 45.5%). Disease Activity Score 28-joint count erythrocyte sedimentation rate (DAS28-ESR) decreased from 5.0 to 2.9 after 24 months (p<0.0001) in patients with RA, and Bath Ankylosing Spondylitis Disease Index score decreased from 5.1 to 2.4 (p<0.0001) in patients with AS. Response rate calculated in patients with PsA by modified Psoriatic Arthritis Response Criteria was 67.9% after 24 months. Most adverse events were of mild or moderate nature, and no new safety signals were detected. According to the physicians' clinical assessments, treatment with GLM was successful (no adverse drug reaction and a clear or moderate therapeutic effect in an individual patient) in 55.0%–56.6% of patients with RA, PsA and AS, respectively, at month 3, increasing from 74.5% to 76.1% at month 24.

Conclusions

GLM subcutaneously once monthly led to substantial improvements in clinical effectiveness in patients with various inflammatory rheumatic diseases who could be followed up in a real-life setting in Germany. The treatment was well tolerated, and the safety profile of GLM was consistent with that observed in the previous randomised controlled trials.

Trial registration number

NCT01313858.

https://ift.tt/2t8Yssb