Medicine by Alexandros G.Sfakianakis: 05/22/18

Τρίτη 22 Μαΐου 2018

Multinational Consensus: Insulin Initiation with Insulin Degludec/Aspart (IDegAsp)

Abstract

Insulin degludec/aspart (IDegAsp) is the first soluble insulin co-formulation, combining a long-acting insulin degludec (IDeg) and rapid-acting insulin aspart (IAsp). In type 2 diabetes patients with oral antidiabetes agent (OAD) inadequacy, insulin initiation with IDegAsp once daily provides superior long-term glycemic control compared to insulin glargine, with similar fasting plasma glucose (FPG) and insulin doses, and numerically lower rates of overall and nocturnal hypoglycemia. Furthermore, in patients with uncontrolled type 2 diabetes previously treated with insulins, IDegAsp twice daily effectively improves glycated hemoglobin and FPG, with fewer hypoglycemic episodes versus premix insulins and basal bolus therapy. In patients with type 1 diabetes mellitus, IDegAsp once daily with two doses of IAsp is a convenient, yet effective, regimen as compared to the conventional 4–5 injection-based basal bolus therapy. IDegAsp is an appropriate and reasonable option for initiation of insulin therapy in both type 1 and type 2 diabetes.

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Safety of Polysorbate 80 in the Oncology Setting

Abstract

Polysorbate 80 is a synthetic nonionic surfactant used as an excipient in drug formulation. Various products formulated with polysorbate 80 are used in the oncology setting for chemotherapy, supportive care, or prevention, including docetaxel, epoetin/darbepoetin, and fosaprepitant. However, polysorbate 80, like some other surfactants, is not an inert compound and has been implicated in a number of systemic and injection- and infusion-site adverse events (ISAEs). The current formulation of intravenous fosaprepitant has been associated with an increased risk of hypersensitivity systemic reactions (HSRs). Factors that have been associated with an increased risk of fosaprepitant-related ISAEs include the site of administration (peripheral vs. central venous), coadministration of anthracycline-based chemotherapy, number of chemotherapy cycles or fosaprepitant doses, and concentration of fosaprepitant administered. Recently, two polysorbate 80-free agents have been approved: intravenous rolapitant, which is a neurokinin 1 (NK-1) receptor antagonist formulated with the synthetic surfactant polyoxyl 15 hydroxystearate, and intravenous HTX-019, which is a novel NK-1 receptor antagonist free of synthetic surfactants. Alternative formulations will obviate the polysorbate 80-associated ISAEs and HSRs and should improve overall management of chemotherapy-induced nausea and vomiting.

Funding Heron Therapeutics, Inc.

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A Chronic Glottic Foreign Body Diagnosed by Radiograph after 9 Months of Symptoms

A six-year-old girl presented to an emergency room after describing choking on a rubber band. She was in no distress and was discharged. Over the course of the next 9 months, she had numerous outpatient and emergency room visits due to intermittent stridor, difficulty breathing, and hoarseness. Eventually, dedicated airway films revealed a laryngeal foreign body. During rigid bronchoscopy, a two-centimeter rubber band was discovered in the larynx. It extended from the supraglottis, through the glottis, and into the subglottis. It was successfully removed. The patient was asymptomatic 24 hours later. This case highlights the appropriate evaluation and management of a child with stridor.

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Long non-coding RNA Gm2199 rescues liver injury and promotes hepatocyte proliferation through the upregulation of ERK1/2

Long non-coding RNA Gm2199 rescues liver injury and promotes hepatocyte proliferation through the upregulation of ERK1/2

Long non-coding RNA Gm2199 rescues liver injury and promotes hepatocyte proliferation through the upregulation of ERK1/2, Published online: 22 May 2018; doi:10.1038/s41419-018-0595-9

Long non-coding RNA Gm2199 rescues liver injury and promotes hepatocyte proliferation through the upregulation of ERK1/2

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Transcriptional and epigenetic modulation of autophagy promotes EBV oncoprotein EBNA3C induced B-cell survival

Transcriptional and epigenetic modulation of autophagy promotes EBV oncoprotein EBNA3C induced B-cell survival

Transcriptional and epigenetic modulation of autophagy promotes EBV oncoprotein EBNA3C induced B-cell survival, Published online: 22 May 2018; doi:10.1038/s41419-018-0668-9

Transcriptional and epigenetic modulation of autophagy promotes EBV oncoprotein EBNA3C induced B-cell survival

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Regulator of chromatin condensation 1 abrogates the G1 cell cycle checkpoint via Cdk1 in human papillomavirus E7-expressing epithelium and cervical cancer cells

Regulator of chromatin condensation 1 abrogates the G1 cell cycle checkpoint via Cdk1 in human papillomavirus E7-expressing epithelium and cervical cancer cells

Regulator of chromatin condensation 1 abrogates the G1 cell cycle checkpoint via Cdk1 in human papillomavirus E7-expressing epithelium and cervical cancer cells, Published online: 22 May 2018; doi:10.1038/s41419-018-0584-z

Regulator of chromatin condensation 1 abrogates the G1 cell cycle checkpoint via Cdk1 in human papillomavirus E7-expressing epithelium and cervical cancer cells

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HMGA1 exacerbates tumor growth through regulating the cell cycle and accelerates migration/invasion via targeting miR-221/222 in cervical cancer

HMGA1 exacerbates tumor growth through regulating the cell cycle and accelerates migration/invasion via targeting miR-221/222 in cervical cancer

HMGA1 exacerbates tumor growth through regulating the cell cycle and accelerates migration/invasion via targeting miR-221/222 in cervical cancer, Published online: 22 May 2018; doi:10.1038/s41419-018-0683-x

HMGA1 exacerbates tumor growth through regulating the cell cycle and accelerates migration/invasion via targeting miR-221/222 in cervical cancer

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Development of muscular dystrophy in a CRISPR-engineered mutant rabbit model with frame-disrupting ANO5 mutations

Development of muscular dystrophy in a CRISPR-engineered mutant rabbit model with frame-disrupting ANO5 mutations

Development of muscular dystrophy in a CRISPR-engineered mutant rabbit model with frame-disrupting <i>ANO5</i> mutations, Published online: 22 May 2018; doi:10.1038/s41419-018-0674-y

Development of muscular dystrophy in a CRISPR-engineered mutant rabbit model with frame-disrupting ANO5 mutations

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Long noncoding RNA gastric cancer-related lncRNA1 mediates gastric malignancy through miRNA-885-3p and cyclin-dependent kinase 4

Long noncoding RNA gastric cancer-related lncRNA1 mediates gastric malignancy through miRNA-885-3p and cyclin-dependent kinase 4

Long noncoding RNA gastric cancer-related lncRNA1 mediates gastric malignancy through miRNA-885-3p and cyclin-dependent kinase 4, Published online: 22 May 2018; doi:10.1038/s41419-018-0643-5

Long noncoding RNA gastric cancer-related lncRNA1 mediates gastric malignancy through miRNA-885-3p and cyclin-dependent kinase 4

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Omission of surgery in older women with early breast cancer has an adverse impact on breast cancer‐specific survival

British Journal of Surgery, EarlyView.

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Cancers, Vol. 10, Pages 154: Treating p53 Mutant Aggregation-Associated Cancer

Cancers, Vol. 10, Pages 154: Treating p53 Mutant Aggregation-Associated Cancer

Cancers doi: 10.3390/cancers10060154

Authors: Mathumai Kanapathipillai

p53 is a tumor suppressor protein. Under stressful conditions, p53 tightly regulates cell growth by promoting apoptosis and DNA repair. When p53 becomes mutated, it loses its function, resulting in abnormal cell proliferation and tumor progression. Depending on the p53 mutation, it has been shown to form aggregates leading to negative gain of function of the protein. p53 mutant associated aggregation has been observed in several cancer tissues and has been shown to promote tumor growth. Recent studies show correlation between p53 mutant aggregation, functional loss, and tumor growth. Moreover, p53 aggregation has been observed in biopsies, patient tissues, and in vivo studies. Given the fact that over fifty percent of cancers have p53 mutation and several of them are prone to aggregation, therapeutic strategies are needed for treating p53 mutant aggregation associated cancers. Recent studies using polyarginine analogues and designer peptides for inhibiting p53 aggregation and tumor growth gives further encouragement in treating cancer as a protein aggregation disease. In this review, we highlight the recent efforts in targeting p53 aggregation in cancer and propose the use of small stress molecules as potential p53-antiaggregation drugs.

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Increased DHRS12 expression independently predicts poor survival in patients with high-grade serous ovarian cancer

Future Oncology, Ahead of Print.

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Lenvatinib and its use in the treatment of unresectable hepatocellular carcinoma

Future Oncology, Ahead of Print.

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Fulvestrant in management of hormone receptor-positive metastatic breast cancer

Future Oncology, Ahead of Print.

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Recent laboratory and clinical findings include the discovery of antibodies to human and mouse neuro-fibrils showing cross-reactivity with Streptococcus spp. and Mycobacterium tuberculosis heat shock proteins (HSP) in NBS. Diagnostically, two distinct magnetic resonance imaging (MRI) patterns of spinal cord involvement have been observed: (a) "Bagel sign" and (b) "motor neuron" patterns. Therapeutic studies have shown that infliximab effectively prevents further relapses and stabilizes the symptoms of patients experiencing ongoing clinical relapses while being treated with single or multiple immunosuppressant drugs.

Summary

Primary neurological involvement referred to as NBS. The majority of patients with NBS present with parenchymal involvement that commonly affects the brain stem-diencephalic region. Headache, dysarthria, ataxia, and hemiparesis are the main clinical features of NBS.

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FDA Tackles Underage E-cigarette Use [News in Brief]

Agency takes steps to prevent retailers from selling to minors, focuses its efforts on JUUL products.

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Machine Learning-Based Radiomics for Molecular Subtyping of Gliomas

Purpose: The new classification announced by the World Health Organization in 2016 recognized five molecular subtypes of diffuse gliomas based on isocitrate dehydrogenase (IDH) and 1p/19q genotypes in addition to histological phenotypes. We aim to determine whether clinical magnetic resonance imaging (MRI) can stratify these molecular subtypes to benefit the diagnosis and monitoring of gliomas. Experimental Design: The data from 456 subjects with gliomas were obtained from The Cancer Imaging Archive. Overall, 214 subjects, including 106 cases of glioblastomas and 108 cases of lower-grade gliomas with preoperative MRI, survival data, histology, IDH, and 1p/19q status were included. We proposed a three-level machine-learning model based on multimodal MR radiomics to classify glioma subtypes. An independent dataset with 70 glioma subjects was further collected to verify the model performance. Results: The IDH and 1p/19q status of gliomas can be classified by radiomics and machine-learning approaches, with areas under receiver operating characteristic curves between 0.922 and 0.975 and accuracies between 87.7 and 96.1% estimated on the training dataset. The test on the validation dataset showed a comparable model performance with that on the training dataset, suggesting the efficacy of the trained classifiers. The classification of 5 molecular subtypes solely based on the MR phenotypes achieved an 81.8% accuracy, and a higher accuracy of 89.2% could be achieved if the histology diagnosis is available. Conclusions: The MR radiomics-based method provides a reliable alternative to determine the histology and molecular subtypes of gliomas.

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Correction to: The European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology Guidelines for the Management of Patients with Cervical Cancer

Two corrections were made to the above publication following its original online publication on 4th May 2018.

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Pericytes in the Premetastatic Niche

The premetastatic niche formed by primary tumor–derived molecules contributes to fixation of cancer metastasis. The design of efficient therapies is limited by the current lack of knowledge about the details of cellular and molecular mechanisms involved in the premetastatic niche formation. Recently, the role of pericytes in the premetastatic niche formation and lung metastatic tropism was explored by using state-of-the-art techniques, including in vivo lineage-tracing and mice with pericyte-specific KLF4 deletion. Strikingly, genetic inactivation of KLF4 in pericytes inhibits pulmonary pericyte expansion and decreases metastasis in the lung. Here, we summarize and evaluate recent advances in the understanding of pericyte contribution to premetastatic niche formation. Cancer Res; 78(11); 1–8. ©2018 AACR.

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Glycosylation of Recombinant Anticancer Therapeutics in Different Expression Systems with Emerging Technologies

Glycosylation, a posttranslational modification, has a major role in recombinant anticancer therapeutic proteins, as most of the approved recombinant therapeutics are glycoproteins. The constant amino acid sequence of therapeutics determines the enzymatic activity, while the presence of glycans influences their pharmacokinetics, solubility, distribution, serum half-life, effector function, and binding to receptors. Glycoproteins expressed in different expression systems acquire their own oligosaccharides, which increases the protein diversity. The heterogeneity of glycans creates hurdles in downstream processing, ultimately leading to variable anticancer therapeutic efficacy. Therefore, glycoproteins require an appropriate expression system to obtain structurally and functionally identical glycans, as in humans. In many expression systems, the N-glycosylation pathway remains conserved in the endoplasmic reticulum, but divergence is observed when the protein enters the Golgi complex. Hence, in recent decades, numerous approaches have been adopted to engineer the Golgi's N-glycosylation pathway to attain human-like glycans. Several researchers have tried to engineer the N-glycosylation pathway of expression systems. In this review, we examine the glycosylation pattern in various expression systems, along with emerging technologies for glycosylation engineering of anticancer therapeutic drugs. Cancer Res; 78(11); 1–12. ©2018 AACR.

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Detection of Bladder Cancer Via Microfluidic Immunoassay and Single-Cell DNA Copy Number Alteration Analysis of Captured Urinary Exfoliated Tumor Cells

The increasing incidence of bladder cancer (BC) and its high rate of recurrence over a 5-year period necessitate the need for diagnosis and surveillance amelioration. Cystoscopy and urinary cytology are the current tools, and molecular techniques such as BTA stat, NMP22, survivin mRNA, and urovysion FISH have attracted attention, however, they suf-fer from insufficient sensitivity or specificity. We developed a novel microfluidic approach for harvesting intact urinary-exfoliated tumor cells (UETCs), either individually or in clus-ters, in a clean and segregated environment, which is crucial to minimize cross-contamination and misreads. To reliably and accurately identify UETC, our quantitative immunoassay involved concurrent use of two oncoproteins CK20 and CD44v6 antigen. CK20 is an intermediate filament protein overexpressed in urothelial tumors, and CD44v6 is a membrane adhesion molecule closely associated with cell invasion, tumor progression and metastatic spread. Single-cell whole-genome sequencing on 12 captured UETCs and copy number alteration analysis showed that 11/12 (91.7%) of the immunofluorescence-identified UETCs possessed genomic instability. A total of 79 BC patients and 43 age-matched normal controls (NC) were enrolled in the study. We detected considerably high-er UETC counts in BC patients versus the NC group [53.3 (10.7-1001.9) vs. 0.0 (0-3.0) UETCs/10 mL; p < 0.0001]. For BC detection, a stratified 10-fold cross-validation of train-ing data reveals an overall predictive accuracy of 0.84 (95%CI: 0.76-0.93) with a 89.8% (95%CI: 71.5-86.4%) for sensitivity and 71.5% (95%CI: 59.7-83.3%) for specificity. Overall, the microfluidic immunoassay demonstrates increased sensitivity and specificity com-pared to other techniques for the detection of bladder cancer.

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Juxtacrine signaling inhibits antitumor immunity by upregulating PD-L1 expression

Programmed death-ligand 1 (PD-L1) is a well-known immune checkpoint protein that helps cancer cells evade immune response. Anti-PD-L1 immune therapy has been approved for the treatment of several advanced human cancers. Therefore, further understanding of the regulatory mechanisms of PD-L1 is critical to improve PD-L1-targeting immunotherapy. Recent studies indicated that contact-dependent pathways may regulate anticancer immunity, highlighting the importance of cell contact-induced signaling in cancer immunity. Here we show that tumor cell contact upregulates PD-L1 expression and reduces T cell-mediated cell killing through the membrane receptor tyrosine kinase ephrin receptor A10 (EphA10), which is not expressed in normal tissues except testis and is known to mediate cell contact-dependent juxtacrine signaling. Knockout of EphA10 in tumor cells increased T cell-mediated antitumor immunity in syngeneic mouse models. EphA10 expression also correlated positively with PD-L1 in human breast tumor tissues. Together our data reveal that in addition to paracrine/autocrine signaling, cell contact-mediated juxtacrine signaling also promotes PD-L1 expression, implying that tumor cells may escape immune surveillance via this mechanism and that targeting EphA10 to boost antitumor immunity may be a new immune checkpoint blockade strategy for female breast cancer patients.

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Mapping the HLA ligandome of Colorectal Cancer Reveals an Imprint of Malignant Cell Transformation

Immune cell infiltrates have proven highly relevant for colorectal carcinoma (CRC) prognosis, making CRC a promising candidate for immunotherapy. Since tumors interact with the immune system via HLA-presented peptide ligands, exact knowledge of the peptidome constitution is fundamental for understanding this relationship. Here we comprehensively describe the naturally presented HLA-ligandome of CRC and corresponding non-malignant colon (NMC) tissue. Mass spectrometry identified 35,367 and 28,132 HLA-class I ligands on CRC and NMC, attributable to 7,684 and 6,312 distinct source proteins, respectively. Cancer-exclusive peptides were assessed on source protein level using Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein analysis through evolutionary relationships (PANTHER), revealing pathognomonic CRC-associated pathways including Wnt, TGF-β, PI3K, p53, and RTK-RAS. Relative quantitation of peptide presentation on paired CRC and NMC tissue further identified source proteins from cancer- and infection-associated pathways to be over-represented merely within the CRC ligandome. From the pool of tumor-exclusive peptides, a selected HLA-ligand subset was assessed for immunogenicity, with the majority exhibiting an existing T cell repertoire. Overall, these data show that the HLA-ligandome reflects cancer-associated pathways implicated in CRC oncogenesis, suggesting that alterations in tumor cell metabolism could result in cancer-specific, albeit not mutation-derived tumor-antigens. Hence, a defined pool of unique tumor peptides, attributable to complex cellular alterations that are exclusive to malignant cells might comprise promising candidates for immunotherapeutic applications.

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Macrophage-derived granulin drives resistance to immune checkpoint inhibition in metastatic pancreatic cancer

The ability of disseminated cancer cells to evade the immune response is a critical step for efficient metastatic progression. Protection against an immune attack is often provided by the tumor microenvironment that suppresses and excludes cytotoxic CD8+ T cells. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive metastatic disease with unmet needs, yet the immunoprotective role of the metastatic tumor microenvironment in pancreatic cancer is not completely understood. In this study we find that macrophage-derived granulin contributes to cytotoxic CD8+ T cell exclusion in metastatic livers. Granulin expression by macrophages was induced in response to colony-stimulating factor-1. Genetic depletion of granulin reduced the formation of a fibrotic stroma, thereby allowing T cell entry at the metastatic site. While metastatic PDAC tumors are largely resistant to anti-PD-1 therapy, blockade of PD-1 in granulin-depleted tumors restored the anti-tumor immune defense and dramatically decreased metastatic tumor burden. These findings suggest that targeting granulin may serve as a potential therapeutic strategy to restore CD8+ T cell infiltration in metastatic PDAC, thereby converting PDAC metastatic tumors, which are refractory to immune checkpoint inhibitors, into tumors that respond to immune checkpoint inhibition therapies.

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Surveillance Frequency Doesn't Cut Mortality in Colorectal Cancer

TUESDAY, May 22, 2018 -- For patients with colorectal cancer after curative surgery, the frequency of surveillance is not associated with mortality; and, the intensity of posttreatment surveillance is not associated with detection of recurrence,...

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Preventing Child Maltreatment Not Yet Feasible in Primary Care

TUESDAY, May 22, 2018 -- The U.S. Preventive Services Task Force (USPSTF) concludes that the evidence is inadequate for primary care interventions to prevent maltreatment. These findings form the basis of a draft recommendation statement published...

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Increase in Pediatric ADHD Meds Exposures from 2000 to 2011

TUESDAY, May 22, 2018 -- From 2000 through 2011 there was an increase in pediatric attention-deficit/hyperactivity disorder (ADHD) medication exposures reported to U.S. poison control centers, according to a study published online May 21 in...

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Post-Surgical Readmissions Higher Among Homeless Veterans

TUESDAY, May 22, 2018 -- Readmissions are higher in homeless veterans discharged to the community after surgery, compared to housed veterans, according to a study published in the June issue of Medical Care. Ashley Titan, M.D., from the VA Palo Alto...

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Procalcitonin Assay Doesn't Cut Antibiotic Use in Lower RTI

TUESDAY, May 22, 2018 -- For patients with suspected lower respiratory tract infection, the provision of procalcitonin assay results does not result in less use of antibiotics than usual care, according to a study published online May 20 in the New...

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Assessment of Quality and Readability of Internet Dietary Information on Irritable Bowel Syndrome

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BLAST-XYPlot Viewer: A Tool for Performing BLAST in Whole-Genome Sequenced Bacteria/Archaea and Visualize Whole Results Simultaneously

One of the most commonly used tools to compare protein or DNA sequences against databases is BLAST. We introduce a web tool that allows the performance of BLAST-searches of protein/DNA sequences in whole-genome sequenced bacteria/archaea, and displays a large amount of BLAST-results simultaneously. The circular bacterial replicons are projected as horizontal lines with fixed length of 360, representing the degrees of a circle. A coordinate system is created with length of the replicon along the x-axis and the number of replicon used on the y-axis. When a query sequence matches with a gene/protein of a particular replicon, the BLAST-results are depicted as an "x,y" position in a specially adapted plot. This tool allows to visualization of the results from the whole data to a particular gene/protein in real time with low computational resources.

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Development of Diagnostic SNP Markers To Monitor Hybridization Between Sika Deer (Cervus nippon) and Wapiti (Cervus elaphus)

Sika deer (Cervus Nippon) and wapiti (Cervus elaphus) are closely related species and their hybridization can result in significant allele-shift of their gene pool. Additive genetic effects and putative heterotic effects of their hybridization on growth performance could confer considerable economic advantage in deer farming. Here, we used double-digest restriction site-associated DNA sequencing technology (ddRAD-seq) and detected ~320,000 genome-wide SNPs from 30 captive individuals: 7 sika deer, 6 wapiti and 17 F1 hybrids (reciprocal cross). By screening observed heterozygosity of each SNP across four taxonomic groups, we report for the first time a resource of 2,015 putative diagnostic SNP markers (species-specific SNPs for sika deer and wapiti), which can be used to design tools for assessing or monitoring the degree of hybridization between sika deer and wapiti. These ddRAD-seq data and SNP datasets are also valuable resources for genome-wide studies, including trait discovery for breeders of domestic deer.

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The prognostic value of systemic inflammation in patients undergoing surgery for colon cancer: comparison of composite ratios and cumulative scores

The prognostic value of systemic inflammation in patients undergoing surgery for colon cancer: comparison of composite ratios and cumulative scores

The prognostic value of systemic inflammation in patients undergoing surgery for colon cancer: comparison of composite ratios and cumulative scores, Published online: 23 May 2018; doi:10.1038/s41416-018-0095-9

The prognostic value of systemic inflammation in patients undergoing surgery for colon cancer: comparison of composite ratios and cumulative scores

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Optimal Management of Prostate Cancer Based on its Natural Clinical History

Prostate cancer is the most common malignancy in males and, despite a marked improvement in diagnostic techniques, a not small percentage of prostate tumours is still diagnosed in advanced stage. It is now clear that prostate cancer passes through distinct phases during its natural history, starting from an initial phase, in which the disease has a locoregional extent, until a very late phase when it becomes refractory to hormone therapy.

It is important to distinguish between local disease, in which tumor may be considered localized in the gland and a systemic disease characterized by high tumor burden and/or dissemination of circulating tumour cells.

All the prostate cancers, at first diagnosis, are characterized by high sensitivity to the androgen deprivation therapy (ADT); however, during the natural history, after a variable period, they become castration resistant. In the past, few therapy options were available for castration resistant prostate cancer, while at present much more approaches can be employed, both hormone-based therapies and chemotherapy regimens. Hypercastration agents are defined as drugs capable to target the androgenandrogen receptor axis even in castrate resistant conditions. Abiraterone and enzalutamide are the only two hypercastration agents available for clinical use.

Osteoclast targeted agents, such as zoledronic acid and denosumab can always been employed, but their use should be limited to the castrate resistant setting.

The optimal understanding of all phases characterizing the natural history of prostate cancer may certainly be useful for the selection of the best therapeutic options in prostate cancer.

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Editorial The Real Impact of Target Therapy in Cancer Patients: Between Hope and Reality

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Meet Our Editorial Board Member

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The Real Impact of Target Therapy in Breast Cancer Patients: Between Hope and Reality

Over the last 15 years, we have seen a huge expansion of the development of drugs directed against biomolecular targets within breast cancer cells. The over-expression of certain receptors (ER, PgR, HER-2, VEGF-R), as well as alteration of several intracellular signal transduction pathways (the PI3K-AKT-mTOR pathway, MEK-MAPK pathway, loss of PTEN, etc ...) has a great impact on the likelihood of recurrence and progression of the disease, influencing the natural history of breast cancer. The recent biomolecular classification of breast cancer (Luminal A / B, HER2- driven, Basal Like) allowed finally to identify specific treatments against molecular target to associate or not to traditional chemotherapy, and to use in relation to the prognosis of the disease. In the following paragraphs, we will set out the major targeted drug that have received indications in breast cancer, both in the localized and in advanced disease, referring to the specific target (hormonal receptors, HER2, VEGF, m-TOR, PARP etc ...).

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Cancer Targeted Therapy Strategy: The Pathologist’s Perspectives

The effectiveness of new personalized treatment procedures in oncology is based on the fact that certain tumors exhibit specific molecular features.

More in detail, neoplastic tissues of patients should display a specific biomarker, most often a specific genetic alteration and/or under/overexpression of a definite protein, that could be the target of its respective drug. Immunohistochemical and molecular analyses, which usually include examination of nucleic acids from either tissues or fluids, are common tests to define the status of a tumor.

This review focuses on the pathologist's role in carefully controlling pre- analytic procedures and standard operating procedures that are a crucial prerequisite to reach reliable and reproducible results. Six paradigmatic applications of targeted therapy, for which pathological diagnosis plays a fundamental role, are summarized. Traditional and next-generation sequencing are also addressed from the pathologist's perspective as well as the importance pathologists have in this shift to more accurate definition of disease risk and prognostication of therapy response in the personalized medicine era.

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Melanoma Adjuvant Treatment: Current Insight and Clinical Features

Melanoma represents 2-3% of all cancers, 95% of them arise from skin, while only 5% are non-cutaneous melanoma. Despite an optimal surgery management, the risk of a local and systemic relapse remains high, particularly in high-risk patients (node-positive or node-negative T3b, T4 a/b). We conducted a systematic review of the main published and ongoing phase I/II/III trials between 2000 and June 2015 on the adjuvant treatment of cutaneous melanoma. The IFN remains the only option currently available for this aim. Ipilimumab represents a possible breakthrough in this setting, considering the positive results of the EORTC 18701 trials in terms of disease free survival (DFS), while data regarding OS are pending. Recent advances in the understanding of the biology of melanoma result in the identification of MAPK pathway role in the melanoma development.

Based on these features, B-RAF inhibitors and their combination with immunotherapy could represent the upcoming therapeutic strategy.

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Current and Emerging Treatments for Metastatic Renal Cell Carcinoma

In the last decades, the treatment of mRCC, metastatic Renal Cell Carcinoma, has become more and more complex due to the approval of a great number of effective systemic treatments that have significantly improved the prognosis of patients suffering from such disease. An additional knowledge of the genetic aberrations and the molecular pathways alterations that underlie RCC, has promoted the development of several novel agents, known as target therapies (TTs). Even though TTs are not curative and all patients eventually progress, an adequate sequencing of these drugs can provide a significant benefit in terms of PFS, Progression Free Survival, and hopefully OS, Overall Survival. To date, there are few data about the optimal sequential use of the TTs hence, in clinical practice, the therapeutic strategy is chosen on the basis of the safety profile of the drug, patients medical history and the pivotal trial results, though such studies often exclude patients with poor performance status and/or severe comorbidities that we routinely see in our clinics. This review aims to provide an overview of the systemic therapies for mRCC both in the newly diagnosed patients and in the subsequent lines of treatment, with a special focus on the last advances about TTs and immunotherapy.

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The Role of Target Therapy in the Treatment of Gastrointestinal Noncolorectal Cancers: Clinical Impact and Cost Consideration

Gastrointestinal (GI) tumors are among the leading cause of death in cancer patients worldwide. Particularly, gastric cancer (GC) is the third cause of cancer deaths, whereas esophageal neoplasm is the eighth leading most common cancer worldwide and its incidence, especially adenocarcinoma type, is continuously increasing. Also, Hepatocellular carcinoma, Cholangiocarcinoma and pancreatic cancer represent a very interesting model to multidisciplinary approach and recently new drugs are used in their treatment. Currently, new clinical trials are designed including classic chemotherapy in association with either small molecule inhibitors (i.e. Tyrosine Kinase inhibitors) and/or monoclonal antibody (i.e. anti-EGFR antibody). Moreover, a comprehensive list of new molecules for target therapy is included in this issue. The development of new treatment modalities (multidisciplinary approach) and targeted therapy approaches have contributed to improving the outcome in these cancer diseases. During the past few years, remarkable progress in molecular biology of malignancy, the discovery of specific targets, and the resulting development of systemic drugs that block critical kinases and several molecular pathways have all contributed to progress in cancer treatment, also in GI non-colorectal cancer treatment.

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Pharmacological Profile and Pharmacogenomics of Anti-Cancer Drugs Used for Targeted Therapy

Background: Drugs for targeted therapies are primarily Small Molecules Inhibitors (SMIs), monoclonal antibodies (mAbs), interfering RNA molecules and microRNA. The use of these new agents generates a multifaceted step in the pharmacokinetics (PK) of these drugs. Individual PK variability is often large, and unpredictability observed in the response to the pharmacogenetic profile of the patient (e.g. cytochome P450 enzyme), patient characteristics such as adherence to treatment and environmental factors.

Objective: This review aims to overview the latest anticancer drugs eligible for targeted therapies and the most recent finding in pharmacogenomics related to toxicity/resistance of either individual gene polymorphisms or acquired mutation in a cancer cell. In addition, an early outline evaluation of the genotyping costs and methods has been taken into consideration.

Future Outlook: To date, therapeutic drug monitoring (TDM) of mAbs and SMIs is not yet supported by heavy scientific evidence. Extensive effort should be made for targeted therapies to better define concentration-effect relationships and to perform comparative randomized trials of classic dosing versus PK-guided adaptive dosing. The detection of individual pharmacogenomics profile could be the key for the oncologists that will have new resources to make treatment decisions for their patients in order to maximize the benefit and minimize the toxicity. Based on this purpose, the clinician should evaluate advantages and limitations, in terms of costs and applicability, of the most appropriate pharmacological approach to performing a tailored therapy.

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Pharmacokinetic Interaction Study of Ketamine and Rhynchophylline in Rat Plasma by Ultra-Performance Liquid Chromatography Tandem Mass Spectrometry

Eighteen Sprague-Dawley rats were randomly divided into three groups: ketamine group, rhynchophylline group, and ketamine combined with rhynchophylline group (n = 6). The rats of two groups received a single intraperitoneal administration of 30 mg/kg ketamine and 30 mg/kg rhynchophylline, respectively, and the third group received combined intraperitoneal administration of 30 mg/kg ketamine and 30 mg/kg rhynchophylline together. After blood sampling at different time points and processing, the concentrations of ketamine and rhynchophylline in rat plasma were determined by the established ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. Chromatographic separation was achieved using a UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 μm) with carbamazepine as an internal standard (IS). The initial mobile phase consisted of acetonitrile and water (containing 0.1% formic acid) with gradient elution. Multiple reaction monitoring (MRM) modes of m/z 238.1 → 179.1 for ketamine, m/z 385.3 → 159.8 for rhynchophylline, and m/z 237.3 → 194.3 for carbamazepine (IS) were utilized to conduct quantitative analysis. Calibration curve of ketamine and rhynchophylline in rat plasma demonstrated good linearity in the range of 1-1000 ng/mL (r > 0.995), and the lower limit of quantification (LLOQ) was 1 ng/mL. Moreover, the intra- and interday precision relative standard deviation (RSD) of ketamine and rhynchophylline were less than 11% and 14%, respectively. This sensitive, rapid, and selective UPLC-MS/MS method was successfully applied to pharmacokinetic interaction study of ketamine and rhynchophylline after intraperitoneal administration. The results showed that there may be a reciprocal inhibition between ketamine and rhynchophylline.

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Isolation and characterization of Bacillus sp. GFP-2, a novel Bacillus strain with antimicrobial activities, from Whitespotted bamboo shark intestine

The abuse of antibiotics and following rapidly increasing of antibiotic-resistant pathogens is the serious threat to our society. Natural products from microorganism are regarded as the important substitution ...

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Diauxic growth of Clostridium acetobutylicum ATCC 824 when grown on mixtures of glucose and cellobiose

Clostridium acetobutylicum, a promising organism for biomass transformation, has the capacity to utilize a wide variety of carbon sources. During pre-treatments of (ligno) cellulose through thermic and/or enzymat...

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Prediction of Central Neuropathic Pain in Spinal Cord Injury Based on EEG Classifier

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Cervical small cell carcinoma frequently presented in multiple high risk HPV infection and often associated with other type of epithelial tumors

Small cell carcinoma of the uterine cervix is a rare and highly malignant tumor, and its etiopathogenesis is strongly related to high-risk HPV infections.

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Prognostic significance of PD-L1 expression and CD8+ T cell infiltration in pulmonary neuroendocrine tumors

Recent research supports a significant role of immune checkpoint inhibitors in the treatment of solid tumors. However, relevant reports for programmed death-ligand 1 (PD-L1) and CD8+ tumor-infiltrating lymphoc...

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An autopsy case of peripheral T cell lymphoma occurring in a postpartum woman: a unique case suggesting changes in the immunocharacteristics of lymphoma cells before and after delivery

The occurrence of malignant lymphoma after delivery is an extremely rare event. Although several cases of Hodgkin lymphoma and B cell lymphoma and a few cases of peripheral T cell lymphoma (PTCL) after deliver...

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Procalcitonin-Guided Use of Antibiotics for Lower Respiratory Tract Infection

The overuse of antibiotic agents is a public health problem associated with increased health care costs and antibiotic resistance. Overuse of antibiotics is common in infections of the lower respiratory tract, where bacterial and viral infections manifest similarly. Procalcitonin is a peptide with…

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The prognostic value of systemic inflammation in patients undergoing surgery for colon cancer: comparison of composite ratios and cumulative scores

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Procalcitonin-Guided Use of Antibiotics for Lower Respiratory Tract Infection

Language used by health care professionals to describe dying at an acute care hospital

To understand the language used to describe the deterioration and death of patients in an acute academic tertiary care centre, and to identify whether patient diagnoses or palliative care(PC) involvement was associated with clearer descriptions of this process.

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Effects of Helicobacter pylori eradication for metachronous gastric cancer prevention: a randomized controlled trial

Whether eradication of Helicobacter pylori (H pylori) reduces incidence of metachronous gastric cancer (MGC) is still debatable. We aimed to evaluate the long-term effect of H pylori eradication on the development of MGC after endoscopic gastric tumor resection.

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Procalcitonin-Guided Use of Antibiotics for Lower Respiratory Tract Infection

These 3 body armor options keep EMS safety top of mind

Choose armor that gives your staff the comfort and flexibility they need to save more lives

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Langerhans cell histiocytosis at L5 vertebra treated with en bloc vertebral resection: a case report

Abstract

Background

Langerhans cell histiocytosis (LCH) in adult lumbar spine is extremely rare, and optimal treatments remain unclear. In literature, only a few cases of lumbar spine LCH were treated using surgery but en bloc vertebral resection has not been used.

Case presentation

A 50-year-old man presented with unbearable radiating pain at his right leg. Radiological studies revealed a solitary osteolytic lesion, which was moderately enhanced on contrast MR imaging and hyper-metabolic on PET/CT, at the right L5 vertebral body and arch. In biopsy, Langerhans cells were observed, but findings were insufficient to establish a diagnosis of LCH. A modified L5 en bloc vertebral resection via anterior and posterior approaches was performed to remove the right 2/3 portion of the L5 vertebra. The left 1/3 vertebral body and left pedicle of L5, which were not affected, were kept in situ to allow short instrumentation and reconstruction. His leg pain disappeared after the surgery, and a precise diagnosis of LCH was established after a throughout histological study of the removed vertebra. The patient further accepted 1 cycle of low-dose radiotherapy postoperatively. At 18-month follow-up, the lumbosacral spine was fused and no local reoccurrence was noticed.

Conclusions

For lumbar spine LCH, surgery should be considered if there are neurological symptoms or histological diagnosis is indefinite in biopsy. En bloc vertebral resection can be used to alleviate neurological symptoms and prevent local reoccurrence.

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Cecal Ligation and Puncture Alters Glucocorticoid Receptor Expression

Objectives: Interventional trials on glucocorticoids in sepsis have yielded capricious results. Recent studies have identified multiple glucocorticoid receptor isoforms. The relative abundance of these isoforms in septic patients and following murine cecal ligation and puncture is unknown. The objective of this study is to determine the effects of cecal ligation and puncture on glucocorticoid receptor isoform abundance. Design: Determination of effects of cecal ligation and puncture on glucocorticoid receptor isoform subtype abundance in C57BL/6 mice. Examination of glucocorticoid receptor isoform abundance in tissues harvested from patients immediately after death from sepsis or nonseptic critical illness. Setting: Research laboratory. Subjects: C57BL/6 mice and human tissue sections from recently deceased critically ill patients. Interventions: C57BL/6 mice were subjected to cecal ligation and puncture or sham operation. Abundance of the activating glucocorticoid receptor α and the inactivating glucocorticoid receptor β isoforms was determined in mouse and human tissue using immunoblotting. Cardiac output with or without stimulation with dexamethasone was assessed using echocardiography. The expression of the gene encoding the glucocorticoid-dependent enzyme glucose-6-phosphatase was identified using polymerase chain reaction. Statistical significance (p

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Cooccurrence of Post-Intensive Care Syndrome Problems Among 406 Survivors of Critical Illness

Objectives: To describe the frequency of cooccurring newly acquired cognitive impairment, disability in activities of daily livings, and depression among survivors of a critical illness and to evaluate predictors of being free of post-intensive care syndrome problems. Design: Prospective cohort study. Setting: Medical and surgical ICUs from five U.S. centers. Patients: Patients with respiratory failure or shock, excluding those with preexisting cognitive impairment or disability in activities of daily livings. Interventions: None. Measurements and Main Results: At 3 and 12 months after hospital discharge, we assessed patients for cognitive impairment, disability, and depression. We categorized patients into eight groups reflecting combinations of cognitive, disability, and mental health problems. Using multivariable logistic regression, we modeled the association between age, education, frailty, durations of mechanical ventilation, delirium, and severe sepsis with the odds of being post-intensive care syndrome free. We analyzed 406 patients with a median age of 61 years and an Acute Physiology and Chronic Health Evaluation II of 23. At 3 and 12 months, one or more post-intensive care syndrome problems were present in 64% and 56%, respectively. Nevertheless, cooccurring post-intensive care syndrome problems (i.e., in two or more domains) were present in 25% at 3 months and 21% at 12 months. Post-intensive care syndrome problems in all three domains were present in only 6% at 3 months and 4% at 12 months. More years of education was associated with greater odds of being post-intensive care syndrome free (p

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How long does numbness last after the dentist?

Going to the dentist for even a simple procedure might require numbing or anesthetic, because the nerves in the teeth are very sensitive. This numb feeling, from Novocaine or other drugs, will last some time after the procedure is finished. Learn more about how long Novocaine lasts, and how to make it wear off faster.

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A Case of Primary Intra-abdominal Synovial Sarcoma

Abstract

Synovial sarcomas are relatively common intermediate-to-high-grade malignant soft tissue tumors, often with an initial indolent course. And among the sarcomas primary intra-abdominal synovial sarcoma is a relatively rare entity that may present with an abdominal mass and diagnosis is usually confirmed by immunohistochemistry. The authors report a case of a 46-year-old man who presented with a large palpable abdominal mass. Contrast-enhanced computed tomography (CT) scan showed a large well-defined heterogeneous intra-abdominal mass filling the entire pelvis and extending upwards till the subhepatic region causing displacement of intra-abdominal organs. However, no other focal lesions were seen in the solid organs. The same findings were confirmed on surgery. Histopathology was suggestive of desmoid tumor/hemangiopericytoma. Immunohistochemistry showed positive markers corresponding to synovial sarcoma. The patient was advised to undergo chemotherapy which was refused and follow-up was lost. After 10 months, patient presented for follow-up CT, which showed marked increase in size of the lesion.

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Social Network, Surgeon, and Media Influence on the Decision to Undergo Contralateral Prophylactic Mastectomy

Objectives: The rate of contralateral prophylactic mastectomy (CPM) has risen sharply in the past decade. The current study was designed to examine social network, surgeon, and media influence on patients' CPM decision-making, examining not only who influenced the decision, and to what extent, but also the type of influence exerted. Methods: Patients (N=113) who underwent CPM at 4 Indiana University–affiliated hospitals between 2008 and 2012 completed structured telephone interviews in 2013. Questions addressed the involvement and influence of the social network (family, friends, and nonsurgeon health professionals), surgeon, and media on the CPM decision. Results: Spouses, children, family, friends, and health professionals were reported as exerting a meaningful degree of influence on patients' decisions, largely in ways that were positive or neutral toward CPM. Most surgeons were regarded as providing options rather than encouraging or discouraging CPM. Media influence was present, but limited. Conclusions: Patients who choose CPM do so with influence and support from members of their social networks. Reversing the increasing choice of CPM will require educating these influential others, which can be accomplished by encouraging patients to include them in clinical consultations, and by providing patients with educational materials that can be shared with their social networks. Surgeons need to be perceived as having an opinion, specifically that CPM should be reserved for those patients for whom it is medically indicated.

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Evaluating Candidacy for Hypofractionated Radiation Therapy, Accelerated Partial Breast Irradiation, and Endocrine Therapy After Breast Conserving Surgery: A Surveillance Epidemiology and End Results (SEER) Analysis

Purpose/Objective(s): After breast conserving surgery, adjuvant radiation therapy represents the standard of care for most patients. However, multiple options exist beyond standard fractionated whole breast irradiation including hypofractionated whole breast irradiation (HFRT), accelerated partial breast irradiation (APBI), and endocrine therapy (ET) alone, which can limit treatment duration, and potentially reduce morbidity and cost. Limited data are available on the percentage of patients eligible for these alternatives; therefore, a Surveillance Epidemiology and End Results (SEER) analysis was performed to assess candidacy for these alternative options in women with early stage breast cancer. Materials and Methods: Women treated for breast cancer between the years of 2010 and 2012 were identified in the SEER database. Patients with unknown staging, metastatic disease, T3/T4 disease, and ≥N1 disease were excluded. Patients were defined as eligible for HFRT based on the American Society for Radiation Oncology (ASTRO) consensus guidelines and randomised trial testing intensity modulated and partial organ radiotherapy following breast conservation surgery for early breast cancer (IMPORT LOW) trial criteria, APBI based on the ASTRO, American Brachytherapy Society and the Groupe Européen de Curiethérapie of European Society for Therapeutic Radiotherapy and Oncology (GEC-ESTRO) consensus guidelines, and GEC-ESTRO APBI and IMPORT LOW trial criteria, and ET alone based on the Cancer and Leukemia Group B 9343 and Post-operative Radiotherapy in Minimum Risk Elderly II inclusion criteria. Results: A total of 108,484 women with early stage breast cancer who met the aforementioned inclusion criteria were identified. Of these patients, 86,896 (80.1%) were eligible for HFRT based on ASTRO consensus guidelines and 81,459 (75.0%) based on IMPORT LOW trial criteria. Regarding APBI, 44,797 (41.2%), 81,020 (74.6%), 81,020 (74.6%) were eligible according to ASTRO, ABS, GEC-ESTRO consensus guidelines, respectively, 97,301 (89.7%) patients according to the GEC-ESTRO trial criteria, and 81,459 (75.0%) patients according to the IMPORT LOW trial criteria. For ET alone, 23,006 (21.2%) were eligible according to Cancer and Leukemia Group B 9343 criteria and 42,104 (38.8%) according to Post-operative Radiotherapy in Minimum Risk Elderly II criteria. Conclusions: This SEER analysis demonstrates that a substantial proportion of women with early stage breast cancer are eligible for HFRT, APBI, or ET alone after breast conserving surgery according to consensus guidelines and prospective trial criteria. With incorporation of additional pathologic, dosimetric, and chemotherapy data, quality assurance pathways may use such data to help ensure patients are receiving appropriate risk stratified treatment recommendations.

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Intraoperative Radiotherapy in the Era of Intensive Neoadjuvant Chemotherapy and Chemoradiotherapy for Pancreatic Adenocarcinoma

Objectives: Improved outcomes with FOLFIRINOX or gemcitabine with nab-paclitaxel in the treatment of metastatic pancreatic adenocarcinoma (PDAC) have prompted incorporation of these regimens into neoadjuvant treatment of locally advanced unresectable PDAC. Whereas some patients remain unresectable on surgical exploration, others are able to undergo resection after intensive neoadjuvant treatment. We evaluated outcomes and toxicity associated with use of intensive neoadjuvant treatment followed by intraoperative radiotherapy (IORT) in combination with resection or exploratory laparotomy. Methods: We retrospectively analyzed patients with locally advanced unresectable or borderline-resectable PDAC who received intensive neoadjuvant treatment with induction chemotherapy and chemoradiotherapy followed by exploratory laparotomy in an IORT-equipped operating suite between 2010 and 2015. Surgical outcomes and overall survival (OS) were compared. Results: Of 68 patients, 41 (60.3%) underwent resection, 18 (26.5%) had unresectable disease, and 9 (13.2%) had distant metastases. Of 41 resectable patients, 22 received IORT for close/positive resection margins on intraoperative frozen section. There was no significant difference in operative times or morbidity with addition of IORT to resection. Median OS was 26.6 months for all patients who underwent resection, 35.1 months for patients who underwent resection and IORT, and 24.5 months for patients who underwent resection alone (P=NS). Of 18 patients with unresectable disease, all but 1 received IORT, with median OS of 24.8 months. IORT was associated with increased hospital stay (4 vs. 3.5 d), but no significant difference in operative times or morbidity. Conclusions: IORT in addition to intensive neoadjuvant chemotherapy and chemoradiotherapy was not associated with increased toxicity when used with resection or exploratory laparotomy, and was associated with encouraging survival rates in patients with close/positive margins and patients with unresectable disease.

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Concurrent Radiotherapy and Triweekly Carboplatin for the Definitive Treatment of Locally Advanced Laryngeal Carcinoma

Purpose of the Study: In 2003, our institution adopted triweekly carboplatin (tCb) area under the curve (AUC) 5 as an alternative to high-dose cisplatin (100 mg/m2) for select patients receiving definitive concurrent chemoradiation for locally advanced laryngeal carcinoma (LALC). Here, we present our experience and outcomes with this definitive concurrent chemoradiation regimen. Methods: From January 2003 through December 2013, 53 patients with stage III (60%) or IVA (40%) LALC were treated with tCb AUC 5 and concurrent radiotherapy to 70 Gy without neoadjuvant chemotherapy. Reasons for using carboplatin instead of cisplatin in these patients were: age 70 and older (21%), poor renal function (6%), presence of 1 or more major comorbid condition(s) (36%), and per discretion of the treating medical oncologist (38%). Primary disease site was glottis in 22 (42%) patients and supraglottis in 31 (58%) patients. Results: Median follow-up time was 63 months for surviving patients. Out of the 53 patients, 43 (81%) received all 3 cycles of carboplatin and all patients received their intended dose of radiotherapy. Although 17 (32%) patients required a feeding tube during treatment, only 2 (4%) required it long term. There were no acute treatment-related grade 4 or 5 hematologic toxicities. On last follow-up, 14 (26%) patients had died of intercurrent disease. For the subgroup of "RTOG 9111 eligible" patients in our cohort (n=46), 5-year estimates of overall survival, disease-free survival, laryngectomy-free survival, larynx preservation, and locoregional control were: 49%, 42%, 39%, 80%, and 63%, respectively. Conclusions: In patients with LALC who are suboptimal candidates for high-dose cisplatin, our experience suggests that tCb AUC 5 with concurrent radiotherapy provides acceptable outcomes with tolerable toxicity.

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Prognostic Factors, Treatment, and Outcomes in Early Stage, Invasive Papillary Breast Cancer: A SEER Investigation of Less Aggressive Treatment in a Favorable Histology

Objectives: Invasive papillary breast cancer (IPBCA) represents 0.5% of invasive BCA, and is thought to carry a favorable prognosis. This population-based study reports on prognostic factors, treatment, and outcomes of early-stage IPBCA to explore whether there is any evidence to support less aggressive treatment. Materials and Methods: IPBCA cases from 1990 to 2009 of the recent Surveillance, Epidemiology, and End Results were analyzed. Inclusion criteria included patients with stage T1-2, N0 IPBCA. Univariate and multivariate analyses were performed using the variables of treatment, stage, race, hormone receptor status, grade (G1-3), and age. Treatment modalities included lumpectomy alone (LA), lumpectomy with radiation treatment (LRT), and mastectomy alone (MA). Results: Among 10,485 patients, median follow-up was 56 months. Five and 10-year overall survival (OS) were 93.1% and 76.8%, respectively. Patients treated with LRT had superior mean OS 16.8 versus 14.9 years for MA (P=0.0004) and 14.2 years for LA (P=0.0003). Improved OS also correlated with lower histologic grade (P

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Knowledge of Clinical Trial Availability and Reasons for Nonparticipation Among Adolescent and Young Adult Cancer Patients: A Population-based Study

Purpose of the Study: Adolescent and young adult (AYA) cancer patients are underrepresented in clinical trials, but the reasons for this phenomenon are unknown. Patients And Methods: Questionnaire and medical record data from 515 AYA cancer patients (21 acute lymphocytic leukemia [ALL], 201 germ cell tumor, 141 Hodgkin lymphoma, 128 non-Hodgkin lymphoma, 24 sarcoma) from a population-based study were analyzed. We used multivariable models to determine characteristics associated with patient knowledge of the availability of clinical trials for their cancer. Reasons for not participating in a trial were tabulated. Results: In total, 63% of patients reported not knowing whether a relevant clinical trial was available, 20% reported knowing that a clinical trial was not available, and 17% reported that a trial was available. Among patients reporting an available trial, 67% were recommended for enrollment. Knowing about the availability of clinical trials was associated with having ALL (odds ratio=2.9, 95% confidence interval=1.1, 7.8). Reporting that a clinical trial was available was positively associated with having ALL, Hodgkin lymphoma, non-Hodgkin lymphoma and sarcoma (relative to germ cell tumor) and working full-time or in school full-time (odds ratio=2.6, 95% confidence interval=1.0, 6.7). Concerns about involvement in research (57%) and problems accessing trials (21%) were the primary reasons cited for not enrolling among patients who knew that a trial was available. Conclusions: Improvement in AYA cancer patient clinical trial enrollment will require enhancing knowledge about trial availability and addressing this population's concerns about participating in medical research.

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Outcomes of Node-positive Breast Cancer Patients Treated With Accelerated Partial Breast Irradiation Via Multicatheter Interstitial Brachytherapy: The Pooled Registry of Multicatheter Interstitial Sites (PROMIS) Experience

Objectives: To report outcomes for breast-conserving therapy using adjuvant accelerated partial breast irradiation (APBI) with interstitial multicatheter brachytherapy in node-positive compared with node-negative patients. Materials and Methods: From 1992 to 2013, 1351 patients (1369 breast cancers) were treated with breast-conserving surgery and adjuvant APBI using interstitial multicatheter brachytherapy. A total of 907 patients (835 node negative, 59 N1a, and 13 N1mic) had >1 year of data available and nodal status information and are the subject of this analysis. Median age (range) was 59 years old (22 to 90 y). T stage was 90% T1 and ER/PR/Her2 was positive in 87%, 71%, and 7%. Mean number of axillary nodes removed was 12 (SD, 6). Cox multivariate analysis for local/regional control was performed using age, nodal stage, ER/PR/Her2 receptor status, tumor size, grade, margin, and adjuvant chemotherapy/antiestrogen therapy. Results: The mean (SD) follow-up was 7.5 years (4.6). The 5-year actuarial local control (95% confidence interval) in node-negative versus node-positive patients was 96.3% (94.5-97.5) versus 95.8% (87.6-98.6) (P=0.62). The 5-year actuarial regional control in node-negative versus node-positive patients was 98.5% (97.3-99.2) versus 96.7% (87.4-99.2) (P=0.33). The 5-year actuarial freedom from distant metastasis and cause-specific survival were significantly lower in node-positive versus node-negative patients at 92.3% (82.4-96.7) versus 97.8% (96.3-98.7) (P=0.006) and 91.3% (80.2-96.3) versus 98.7% (97.3-99.3) (P=0.0001). Overall survival was not significantly different. On multivariate analysis age 50 years and below, Her2 positive, positive margin status, and not receiving chemotherapy or antiestrogen therapy were associated with a higher risk of local/regional recurrence. Conclusions: Patients who have had an axillary lymph node dissection and limited node-positive disease may be candidates for treatment with APBI. Further research is ultimately needed to better define specific criteria for APBI in node-positive patients.

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A Phase II Study to Prevent Radiation-induced Rectal Injury With Lovastatin

Purpose: Physician reported symptomatic late rectal injury occurs in about 5% to 25% of patients treated with radiation therapy for prostate cancer, depending on the treatment technique. Patients, however, report clinically meaningful declines in bowel/rectal function regardless of the technique used. Lovastatin has been shown to protect mice from late radiation injury. This study was designed to determine if lovastatin might reduce the incidence of late rectal injury in patients receiving radiation therapy for prostate cancer. Materials and Methods: Patients with adenocarcinoma of the prostate receiving radiotherapy with curative intent were eligible. A portion of the rectum had to receive at least 60 Gy. Gastrointestinal functioning was assessed using both physician-reported and patient-reported instruments at baseline and at prescribed intervals during and after treatment. Lovastatin (20 to 80 mg/d) was started on day 1 of radiation and continued for 12 months. Patients were followed for an additional 12 months. The primary endpoint was physician-reported rectal toxicity ≥grade 2 during the first 2 years after treatment. Results: A total of 20/53 (38%) patients developed grade 2 or higher toxicity during the 2-year follow-up period. Seventeen patients had 1 or more unresolved gastrointestinal symptom at the end of 2 years, 3 (6%) of which were grade 2 and none were of higher grade. Conclusions: The primary endpoint of the study was not met. Lovastatin, as administered in this trial, did not reduce the incidence of grade 2 or higher rectal toxicity compared with historical controls.

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Decreased Risk of Radiation Pneumonitis With Coincident Concurrent Use of Angiotensin-converting Enzyme Inhibitors in Patients Receiving Lung Stereotactic Body Radiation Therapy

Objectives: Angiotensin-converting enzyme inhibitors (ACEi) have demonstrated decreased rates of radiation-induced lung injury in animal models and clinical reports have demonstrated decreased pneumonitis in the setting of conventionally fractionated radiation to the lung. We tested the role of ACEi in diminishing rates of symptomatic (grade ≥2) pneumonitis in the setting of lung stereotactic body radiation therapy (SBRT). Methods: We analyzed patients treated with thoracic SBRT to 48 to 60 Gy in 4 to 5 fractions from 2006 to 2014. We reviewed pretreatment and posttreatment medication profiles to document use of ACEi, angiotensin receptor blockers, bronchodilators, aspirin, PDE-5 inhibitors, nitrates, and endothelin receptor antagonists. Pneumonitis was graded posttreatment based on Common Terminology Criteria for Adverse Events Version 4.0. Univariate and multivariate analysis was performed and time to development of pneumonitis was evaluated by the Kaplan-Meier method. Results: A total of 189 patients were evaluated with a median follow-up of 24.8 months. The overall 1-year rate of symptomatic pneumonitis was 13.2%. The 1-year rate of symptomatic pneumonitis was 4.2% for ACEi users versus 16.3% in nonusers (P=0.03). On univariate analysis, the odds of developing grade 2 or greater pneumonitis were significantly lower for patients on ACEi (P=0.03). On multivariate analysis, after controlling for clinicopathologic characteristics and dosimetric endpoints, there was a significant association between ACEi use and decreased risk of clinical pneumonitis (P=0.04). Angiotensin receptor blockers or other bronchoactive medications did not show significant associations with development of pneumonitis. Conclusions: Incidental concurrent use of ACEi demonstrated efficacy in diminishing rates of symptomatic pneumonitis in the setting of lung SBRT.

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Does Specialty Bias Trump Evidence in the Management of High-risk Prostate Cancer?

Objective: The objective was to query how specialty influences treatment recommendations for high-risk prostate cancer in 3 clinical settings: upfront management, postoperative management, and management of biochemical recurrences (BCRs) after radiotherapy (RT). We hypothesized that specialty bias would manifest in all settings, trumping available evidence. Methods: A survey of practicing urologists and radiation oncologists was distributed through electronic mail. Questions pertained to upfront management, postoperative treatment, and local salvage for postradiation BCRs. The associations between 26 selected categorical responses and specialty were assessed using multivariate logistic regression. Training level/expertise, practice setting, percentage of consultation caseload consisting of prostate cancer, and nationality were set as effect modifiers. Results: One thousand two hundred fifty-three physicians (846 radiation oncologists and 407 urologists) completed the survey. Radiation oncologists were more likely to recommend adjuvant RT and consider it to be underutilized, and more likely to recommend salvage RT at lower prostate-specific antigen thresholds (P

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Preradiation Chemotherapy for Adult High-risk Medulloblastoma: A Trial of the ECOG-ACRIN Cancer Research Group (E4397)

Objectives: To assess the long-term outcomes and objective response (OR) to preradiation chemotherapy and radiation in adult high-risk medulloblastoma. Materials and Methods: In this prospective phase II trial, adults with high-risk medulloblastoma were treated with 3 cycles of preradiation cisplatin, etoposide, cyclophosphamide, and vincristine followed by craniospinal radiation (CSI). OR, progression-free survival (PFS), overall survival (OS), and toxicities were assessed. Results: Eleven patients were enrolled over a 6-year period. Six (55%) had subarachnoid metastases. Two (18%) had an OR to preradiation chemotherapy. Two (18%) progressed while on chemotherapy. Completion of CSI was not compromised. The OR rate after chemotherapy and radiation was 45% (5/11). Nonevaluable patients at both time-points weakened the response data conclusions. Median PFS was 43.8 months. Five-year PFS was 27%. Five-year OS was 55%. Nonmetastatic (M0) and metastatic (M+) patients had similar outcomes. Conclusions: The OR to this preradiation chemotherapy regimen is lower than anticipated from the adult and pediatric literature raising a question about comparative efficacy of chemotherapy in different age groups. The OS achieved is similar to retrospective adult series, but worse than pediatric outcomes. Although this regimen can be administered without compromising delivery of CSI, our results do not provide support for the use of this neoadjuvant chemotherapy for adult medulloblastoma.

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Patient-reported Urinary, Bowel, and Sexual Function After Hypofractionated Intensity-modulated Radiation Therapy for Prostate Cancer: Results From a Randomized Trial

Objectives: Hypofractionated prostate radiotherapy may increase biologically effective dose delivered while shortening treatment duration, but information on patient-reported urinary, bowel, and sexual function after dose-escalated hypofractionated radiotherapy is limited. We report patient-reported outcomes (PROs) from a randomized trial comparing hypofractionated and conventional prostate radiotherapy. Methods: Men with localized prostate cancer were enrolled in a trial that randomized men to either conventionally fractionated intensity-modulated radiation therapy (CIMRT, 75.6 Gy in 1.8 Gy fractions) or to dose-escalated hypofractionated IMRT (HIMRT, 72 Gy in 2.4 Gy fractions). Questionnaires assessing urinary, bowel, and sexual function were completed pretreatment and at 2, 3, 4, and 5 years after treatment. Results: Of 203 eligible patients, 185 were evaluable for PROs. A total of 173 completed the pretreatment questionnaire (82 CIMRT, 91 HIMRT) and 102 completed the 2-year questionnaire (46 CIMRT, 56 HIMRT). Patients who completed PROs were similar to those who did not complete PROs (all P>0.05). Patient characteristics, clinical characteristics, and baseline symptoms were well balanced between the treatment arms (all P>0.05). There was no difference in patient-reported bowel (urgency, control, frequency, or blood per rectum), urinary (dysuria, hematuria, nocturia, leakage), or sexual symptoms (erections firm enough for intercourse) between treatment arms at 2, 3, 4, and 5 years after treatment (all P>0.01). Concordance between physician-assessed toxicity and PROs varied across urinary and bowel domains. Discussion: We did not detect an increase in patient-reported urinary, bowel, and sexual symptom burden after dose-escalated intensity-modulated prostate radiation therapy using a moderate hypofractionation regimen (72 Gy in 2.4 Gy fractions) compared with conventionally fractionated radiation.

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Pretreatment Tumor Thickness as a Predictor of Pathologic Complete Response to Neoadjuvant Chemoradiation Therapy for Stage II/III Rectal Adenocarcinoma

Objectives: To evaluate pretreatment tumor thickness in predicting pathologic complete response (pCR) of stage II/III rectal adenocarcinoma to neoadjuvant chemoradiation (chemoradiotherapy [CRT]). Methods: We retrospectively analyzed 185 patients who were diagnosed with stage II or III rectal adenocarcinoma from January 2011 to July 2013 and treated with neoadjuvant intensity-modulated radiation therapy (45 Gy in 1.8-Gy fractions to pelvis and 50 Gy in 2-Gy fractions to rectal tumor as an integrated boost) or 3 dimensionally conformal radiation therapy (45 Gy in 1.8-Gy fractions to pelvis followed by an additional 5.4-Gy to rectal tumor) concurrently with two 3-week cycles of chemotherapy (oxaliplatin 130 mg/m2 on day 1 and capecitabine 825 mg/m2, twice per day from day 1 to 14, cycle 2 starts on week 4). One week after CRT, 36% patients received 1 more cycle of the above chemotherapy and 55% received 1 to 2 cycles of FOLFOX6. Tumor response was categorized as pCR and non-pCR. Tumor thickness measured on magnetic resonance imaging was collected. A multivariate logistic regression model was used to evaluate the association of potential predictors and pCR. Results: Thirty-eight patients (20.5%) reached pCR. Multivariate analysis found the pretreatment tumor thickness to be associated with higher probability of pCR after adjusting for radiation therapy-surgery interval time and pretreatment carcino-embryonic antigen level. The pretreatment carcino-embryonic antigen level was associated with pCR in the univariate analysis but lost the association in the multivatiate model. The pretreatment T or N stage, tumor volume, distance from tumor to anal verge, craniocaudal length of tumor, radiation therapy technique, and patient age and sex were not associated with pCR. Conclusions: We concluded that pretreatment tumor thickness is an independent predictor for pCR of stage II/III rectal adenocarcinoma to the neoadjuvant CRT.

https://ift.tt/2ICOmGq

Stereotactic Ablative Radiotherapy (SABR) for Large Renal Tumors: A Retrospective Case Series Evaluating Clinical Outcomes, Toxicity, and Technical Considerations

Objectives: Metastatic renal cell carcinoma represents a clinical scenario where aggressive treatment to the primary tumor (ie, cytoreductive nephrectomy) is associated with a survival benefit. We hypothesized that stereotactic ablative radiotherapy (SABR) could be a safe alternative local modality for inoperable metastatic renal cell carcinoma patients. Our study objectives were to report on technical considerations, toxicity, and clinical outcomes of our institutional experience with renal SABR. Materials and Methods: Patients who underwent renal SABR at our institution between January 2008 and June 2015 were reviewed. Toxicity was quantified using the Common Terminology Criteria for Adverse Events version 4.0. Radiographic response was evaluated using the Response Evaluation Criteria in Solid Tumors classification. Median overall survival and follow-up were calculated using the Kaplan-Meier and reverse Kaplan-Meier methods, respectively. Results: We identified 11 patients that met study criteria. SABR was directed to the tumor or whole kidney in 5 fractions to a dose of 25 to 40 Gy. Median tumor diameter and planning target volume were 9.5 cm (range, 7.5 to 24.4) and 819.3 cm3 (range, 313.4 to 5704.3), respectively. Median follow-up was 3.9 years (95% confidence interval, 0.6-4.9). Five cases of grade 1 toxicity were reported. In the patient with the largest target, grade 2 diarrhea and probable grade 3 nausea were observed. In patients with available follow-up imaging (7/11), stable disease (n=5), partial response (n=1), and progressive disease (n=1) were observed. Median overall survival was 20.4 months (95% confidence interval, 2.30-N/A). Conclusions: In this small cohort, renal SABR was delivered with minimal toxicity. A prospective study is underway at our institution to determine maximum tolerable and optimal dosing (NCT02264548).

https://ift.tt/2s2qoOw

Molecular Predictors of Response to Neoadjuvant Chemoradiation for Rectal Cancer

Objectives: To determine whether the expression of specific molecular markers in the rectal cancer biopsies prior to treatment, can correlate with complete tumor response to chemoradiotherapy (CRT) as determined by the pathology of the surgical specimen. Methods: We retrospectively examined pretreatment rectal biopsies of patients aged 18 years or older with locally advanced rectal cancer who had been treated with neoadjuvant CRT and surgical resection in our tertiary-care, university-affiliated medical center, between January 2001 and December 2011. Samples were analyzed for expression of B-cell lymphoma 2, P53, Ki67, epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor, and the tumor regression grade after CRT and radical surgery. Results: Forty-seven patients were included in the final analysis. Main outcome measures were the correlation between the expression of the molecular markers tested in the pretreatment biopsy, and complete tumor response. Complete pathologic response after CRT was attained in 27% of the patients. Percentage of cells expressing EGFR in the pretreated biopsies of patients having complete pathologic response after CRT and surgery was 33.08±7.87% compared to 19±15.36% (P=0.38), 6.66±2.83% (P

https://ift.tt/2IEPXLP

Under the Knife: The History of Surgery in 28 Remarkable Operations

No abstract available

https://ift.tt/2KNX0mh

Identifying Barriers to Implementation of the National Partnership for Maternal Safety Obstetric Hemorrhage Bundle at a Tertiary Center: Utilization of the Delphi Method

BACKGROUND: In 2015, the National Partnership for Maternal Safety (NPMS) developed an obstetric hemorrhage consensus bundle to provide birthing facilities in the United States with consistent, validated practice guidelines for postpartum hemorrhage management. The process of implementing each bundle element at a large tertiary labor and delivery unit has not been described; we sought to identify practice deficiencies and perceived barriers to bundle implementation among multidisciplinary providers. METHODS: We conducted a prospective, cross-sectional, consensus-building study based on the Delphi method. A multidisciplinary expert panel comprised of anesthesiologists, obstetricians, nurses, and surgical technicians was assembled and participated in 4 sequential questionnaires. The first round identified bundle elements that experts determined as not currently adequate and perceived barriers to implementation. The second round established prioritization of elements within each professional group; and the third round ranked the elements with at least 60% agreement on feasibility of implementation and positive impact on patient care. The last round revealed responses across all 4 professional groups to derive a final consensus. Descriptive statistics were performed. RESULTS: A total of 38 experts completed the study (11 anesthesiologists, 11 obstetricians, 10 nurses, and 6 surgical technicians). While all 13 (100%) NPMS obstetric bundle elements were described as deficient in our labor and delivery unit by a provider in at least 1 discipline, consensus among at least 3 of the 4 disciplines was achieved for 6 element deficiencies. Barriers to implementation were determined. The initiatives that achieved consensus as possessing high patient impact and implementation feasibility were protocol-driven management, unit-based simulation drills, blood loss quantification, and team huddles and debriefings. CONCLUSIONS: The NPMS obstetric hemorrhage bundle was created to help guide practice and systems improvement for US birthing facilities. The Delphi method enabled identification of deficient elements and perceived barriers to element implementation, as well as group consensus on elements with highest patient impact and feasibility. Multidisciplinary group consensus can identify deficiencies and promote tangible, quality improvements in a large, tertiary-care labor and delivery unit. Institutions may utilize our described technique to guide implementation of future care bundles. Accepted for publication April 12, 2018. Funding: Departmental. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). Institutional Research Ethics Board: Partners HealthCare Institutional Review Board, Partners Human Research Committee, 116 Huntington Ave, Suite 1002, Boston, MA 02116. Clinical trial number and registry URL: NCT03018119 https://ift.tt/2IIP98H. Reprints will not be available from the authors. Address correspondence to Annemaria De Tina, MD, FRCPC, Department of Anesthesiology, McMaster University, Third Floor, 237 Barton St E, Hamilton, ON L8L 2X2, Canada. Address e-mail to detinaa@mcmaster.ca. © 2018 International Anesthesia Research Society

https://ift.tt/2s0UBOd

Organ Donation After Circulatory Death: Ethical Issues and International Practices

Donation after circulatory death (DCD) is an increasingly utilized practice that can contribute to reducing the difference between the supply of organs and the demand for organs for transplantation. As the number of transplanted organs from DCD donors continues to increase, there is an essential need to address the ethical aspects of DCD in institutional DCD protocols and clinical practice. Ethical issues of respecting the end-of-life wishes of a potential donor, respecting a recipient's wishes, and addressing potential conflicts of interest are important considerations in developing policies and procedures for DCD programs. Although there may be diversity among DCD programs in Europe, Australia, Israel, China, the United States, and Canada, addressing ethical considerations in these DCD programs is essential to respect donors and recipients during the altruistic and generous act of organ donation. Accepted for publication April 12, 2018. Funding: None. The author declares no conflicts of interest. Reprints will not be available from the author. Address correspondence to Barbara G. Jericho, MD, FASA, Department of Anesthesiology, University of Illinois Hospital and Health Sciences System, 1740 W Taylor St, Suite 3200, M\C 515, Chicago, IL 60612. Address e-mail to jericho@uic.edu. © 2018 International Anesthesia Research Society

https://ift.tt/2rZKY2e

“Modified Dynamic Needle Tip Positioning” Short-Axis, Out-of-Plane, Ultrasound-Guided Radial Artery Cannulation in Neonates: A Randomized Controlled Trial

BACKGROUND: Radial artery cannulation is extremely challenging in neonatal patients. Herein, we compared the success rate of the modified dynamic needle tip positioning short-axis, out-of-plane, ultrasound-guided technique with that of the traditional palpation technique in neonatal radial artery cannulation. METHODS: Sixty term neonates undergoing major abdominal surgery were randomized into the ultrasound or palpation group via the sealed-envelope method. The ultrasound group underwent radial artery cannulation using an ultrasonic apparatus, while traditional palpation of arterial pulsation was used in the palpation group. The arterial diameter and depth were measured on ultrasound before the puncture. We recorded age, weight, sex, and other background characteristics. The primary outcomes included the first-attempt, total success rates, and the total puncture procedure duration. Secondary outcomes included the incidence of complications (hematoma and thrombosis). Data were compared between the 2 groups. RESULTS: Sixty term neonates were enrolled in the study. The success rates of the first attempt in the ultrasound and palpation groups were 40% (n = 30) and 10% (n = 30), respectively (P = .007; relative risk, 4.0; 95% confidence interval, 1.3–12.8). The total success rate was 96.7% in the ultrasound group and 60.0% in the palpation group (P = .001; relative risk, 1.61; 95% confidence interval, 1.19–2.17). The average time to accomplish radial artery cannulation in the ultrasound and palpation groups was 91.4 ± 55.4 and 284.7 ± 153.6 seconds, respectively (P

https://ift.tt/2KLu0vb

The Effect of Dexmedetomidine on Propofol Requirements During Anesthesia Administered by Bispectral Index-Guided Closed-Loop Anesthesia Delivery System: A Randomized Controlled Study

BACKGROUND: Dexmedetomidine, a selective α2-adrenergic agonist currently approved for continuous intensive care unit sedation, is being widely evaluated for its role as a potential anesthetic. The closed-loop anesthesia delivery system (CLADS) is a method to automatically administer propofol total intravenous anesthesia using bi-spectral index (BIS) feedback and attain general anesthesia (GA) steady state with greater consistency. This study assessed whether dexmedetomidine is effective in further lowering the propofol requirements for total intravenous anesthesia facilitated by CLADS. METHODS: After ethics committee approval and written informed consent, 80 patients undergoing elective major laparoscopic/robotic surgery were randomly allocated to receive GA with propofol CLADS with or without the addition of dexmedetomidine. Quantitative reduction of propofol and quality of depth-of-anesthesia (primary objectives), intraoperative hemodynamics, incidence of postoperative adverse events (sedation, analgesia, nausea, and vomiting), and intraoperative awareness recall (secondary objectives) were analyzed. RESULTS: There was a statistically significant lowering of propofol requirement (by 15%) in the dexmedetomidine group for induction of anesthesia (dexmedetomidine group: mean ± standard deviation 0.91 ± 0.26 mg/kg; nondexmedetomidine group: 1.07 ± 0.23 mg/kg, mean difference: 0.163, 95% CI, 0.04–0.28; P = .01) and maintenance of GA (dexmedetomidine group: 3.25 ± 0.97 mg/kg/h; nondexmedetomidine group: 4.57 ± 1.21 mg/kg/h, mean difference: 1.32, 95% CI, 0.78–1.85; P

https://ift.tt/2rZKPvI

Prevalence and antimicrobial susceptibility patterns of extended spectrum beta-lactamase producing Entrobacteriaceae in the University of Gondar Referral Hospital environments, northwest Ethiopia

This study aimed at assessing the magnitude, distribution, and the antimicrobial susceptibility of the extended spectrum beta-lactamase producing Entrobacteriaceae in the University of Gondar Referral Hospital en...

https://ift.tt/2KMOEuS

VEGF vascularization pathway in human intervertebral disc does not change during the disc degeneration process

During degeneration of the intervertebral disc ingrowth of blood vessels and nerves into the disc are associated with back pain. Vascular endothelial growth factors promote vasculogenesis by binding to the mem...

https://ift.tt/2J2DEMT

Spontaneous splenic rupture complicating primary varicella zoster infection: a case report

Primary varicella zoster virus (VZV) infection is a common illness, predominantly affecting children. Its course is typically benign, although severe complications have been described. Splenic rupture is an ex...

https://ift.tt/2GDLpUl

Perceived behavioural predictors of late initiation to HIV/AIDS care in Gurage zone public health facilities: a cohort study using health belief model

The study was aimed to measure incidence density rate and identify perceived behavioural believes of late initiation to HIV/AIDS care in Gurage zone public health facilities from September 2015 to November 2016.

https://ift.tt/2Losalg

Belatacept in Solid Organ Transplant: Review of Current Literature Across Transplant Types

Calcineurin inhibitors (CNIs) have been the backbone immunosuppressant for solid organ transplant recipients for decades. Long-term use of CNIs unfortunately is associated with multiple toxicities, with the biggest concern being CNI-induced nephrotoxicity. Belatacept is a novel agent approved for maintenance immunosuppression in renal transplant recipients. In the kidney transplant literature, it has shown promise as being an alternative agent by preserving renal function and having a minimal adverse effect profile. There are emerging studies of its use in other organ groups, particularly liver transplantation, as well as using with other alternative immunosuppressive strategies. The purpose of this review is to analyze the current literature of belatacept use in solid organ transplantation and discuss its use in current practice. Corresponding author: Caroline P. Perez, PharmD, BCPS, Clinical Pharmacy Specialist, Solid Organ Transplant, Medical University of South Carolina, 150 Ashley Avenue, MSC 584, Charleston, SC 29425. perezca@musc.edu Authorship contribution: All authors were involved with analyzing the literature, interpreting the data, and writing the manuscript. CP, NP, and NAP were involved with revising the manuscript. CP was involved with coordination and final editing of the manuscript. All authors agreed upon final approval of the version submitted. Disclosure: The authors declare no conflicts of interest. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2IYNHCF

Three-electrode Coin Cell Preparation and Electrodeposition Analytics for Lithium-ion Batteries

Three-electrode cells are useful in studying the electrochemistry of lithium-ion batteries. Such an electrochemical setup allows the phenomena associated with the cathode and anode to be decoupled and examined independently. Here, we present a guide for construction and use of a three-electrode coin cell with emphasis on lithium plating analytics.

https://ift.tt/2GI8jK2

A Fast and Quantitative Method for Post-translational Modification and Variant Enabled Mapping of Peptides to Genomes

Here we present the proteogenomic tool PoGo and protocols for fast, quantitative, post-translational modification and variant enabled mapping of peptides identified through mass spectrometry onto reference genomes. This tool is of use to integrate and visualize proteogenomic and personal proteomic studies interfacing with orthogonal genomics data.

https://ift.tt/2LjM68K

Early TLR4 blockade attenuates sterile inflammation-mediated stress in islets during isolation and promotes successful transplant outcomes

Background During the isolation process, pancreatic islets are exposed to an environment of sterile inflammation resulting in an upregulated inflammatory state prior to transplantation. Toll-like receptor 4 (TLR4) has been identified as a major mediator of sterile inflammation. Therefore, we sought to determine whether early TLR4 blockade would be effective in reducing the inflammatory burden in islets pretransplant. Methods Islets from C57BL/6 mice were treated with a TLR4 antagonist during the pancreatic ductal perfusion and digestion steps of the isolation process. Islets were then analyzed for inflammation by RT-PCR and western blot, and for viability and function in vitro. A syngeneic transplant model using a marginal mass of islets transplanted intraportally into mice with streptozotocin-induced diabetes was used to study transplant outcomes after early TLR4 blockade. Results Diabetic mice receiving 150 islets treated with early TLR4 blockade achieved euglycemia at a higher rate than mice receiving untreated islets (75% vs 29%; p

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Survival and Metabolic Function of Syngeneic Mouse Islet Grafts Transplanted into the Hepatic Sinus-tract

Background Islet grafts are transplanted into the liver via a portal vein in 90% of the clinical islet transplantations. However, the portal vein is far from being the ideal infusion site due to its unique drawbacks. These issues necessitated the exploration of an alternatively optimized site for clinical islet transplantation. With the widespread clinical application of percutaneous transhepatic puncture technique, we envisioned the possibility of islet transplantation into the hepatic sinus-tract (HST). Methods The HST was created by temporarily placing a medically approved material into the hepatic parenchyma of C57BL/6 mice. The syngeneic islets were transplanted into the HST, following which, the nonfasting blood glucose, intraperitoneal glucose tolerance, and morphology were evaluated. Results A collagen-lined HST was formed by the 28-day implantation of a cylindrical nylon rod. Transplantation of ~300 syngeneic islets into the HST routinely reversed the hyperglycemia of the recipient mice and maintained normoglycemia for >100 days until the graft was removed. The islet grafts within the HST stained positively for insulin, glucagon, and abundant microvessels and achieved comparable results to the islet grafts under the kidney capsule (KC) with respect to glycemic control and glucose tolerance. Conclusions These results suggested that an HST can be constructed for islet transplantation by temporarily placing a nylon material in the liver parenchyma. The HST is a promising site for clinical islet transplantation, thereby providing a satisfactory environment for the survival and metabolic function of islet grafts. Corresponding author Jialin Zhang, MD, PhD, Hepatobiliary Surgery Department and Unit of Organ Transplantation, the First Hospital of China Medical University, Shenyang 110001, China. Tel: 86-24-83283310. Fax: 86-24-83282997. Email: jlz2000@yeah.net Contribution: F.L participated in the research design, performance of the research, data analysis and writing of the manuscript. A.J, X.L, C.Z and N.S participated in the performance of the research and writing of the manuscript. J.Z participated in research design and writing of the manuscript. Disclosure Statement The authors report no conflicts of interest and are solely responsible for the content and writing of this manuscript. Financial Support: This work was supported by the National Natural Science Foundation of China (NSFC) (no. 31370989). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Τρίτη 22 Μαΐου 2018

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