Immunological classification of renal cell carcinoma patients based on phenotypic analysis of immune check-point molecules

Abstract

Objectives

To clarify comprehensive immunological signature patterns of tumour tissue-infiltrating lymphocytes in patients with renal cell carcinoma and show its clinical significance.

Materials and methods

We investigated the surface marker expressions of tumour tissue-infiltrating lymphocytes quantitatively and classified them based on their functional populations. We extracted 109 sets of tumour tissue-infiltrating lymphocytes from 80 patients who underwent surgical resection of renal cell carcinoma, of which 44 tumour tissue-infiltrating lymphocytes were multiply extracted from 15 patients. Each tumour tissue-infiltrating lymphocyte was characterised on the basis of functional T-cell populations using ten surface marker expressions measured by flow cytometry.

Results

All sets of the tumour tissue-infiltrating lymphocytes were classified into three groups, which correlated significantly with Fuhrman grade (OR 0.253, 95% CI 0.094–0.678, P = 0.006). Importantly, both overall metastasis-free survival (HR 0.449, 95% CI 0.243–0.832, P = 0.011) and recurrence-free survival (HR 0.475, 95% CI 0.238–0.948, P = 0.035) of the patients with the higher marker expressions were significantly inferior to those of the patients with the lower marker expressions by multivariate analysis. Six specific genes for this classification identified by microarray analysis verified our results using the TCGA KIRC data set. In addition, we discovered the presence of intra-tumoural diversity in the classification of 3 (20%) of the 15 patients.

Conclusions

This study showed that the presence of classable diversity in the immunological signature of tumour tissue-infiltrating lymphocytes correlated with prognosis and tumour aggressiveness that was observed even within individual tumours in some patients with renal cell carcinoma.

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Intraoperative naloxone reduces remifentanil-induced postoperative hyperalgesia but not pain: a randomized controlled trial

Abstract

Background

Intraoperative use of a high-dose remifentanil may induce postoperative hyperalgesia. Low-dose naloxone can selectively reverse some adverse effects of opioids without compromising analgesia. We thus hypothesized that the intraoperative use of a high-dose remifentanil combined with a low-dose naloxone infusion reduces postoperative hyperalgesia compared with the use of remifentanil alone.

Methods

Patients undergoing elective thyroid surgery were randomly assigned into one of three groups, depending on the intraoperative effect-site concentration of remifentanil, with or without a continuous infusion of naloxone: 4 ng ml⁻¹ remifentanil with 0.05 μg kg⁻¹ h⁻¹ naloxone in the high-remifentanil with naloxone group, and 4 or 1 ng ml⁻¹ remifentanil with a placebo in the high- or low-remifentanil groups, respectively. We measured the pain thresholds (primary outcome) to mechanical stimuli using von Frey filaments and incidence of hyperalgesia on the peri-incisional area 24 h after surgery. We also measured pain intensity, analgesic consumptions and adverse events up to 48 h after surgery.

Results

The pain threshold presented as von Frey numbers [median (interquartile range)] was significantly lower in the high-remifentanil group (n=31) than in the high-remifentanil with naloxone (n=30) and the low-remifentanil (n=30) groups [3.63 (3.22–3.84) vs 3.84 (3.76–4.00) vs 3.80 (3.69–4.08), P=0.011]. The incidence of hyperalgesia was also higher in the high-remifentanil group than in the other groups [21/31 vs 10/30 vs 9/30, P=0.005]. Postoperative pain intensity, analgesic consumptions and adverse events were similar between groups.

Conclusions

The intraoperative use of low-dose naloxone combined with high-dose remifentanil reduced postoperative hyperalgesia but not pain.

Clinical trial registration

NCT02856087.

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Role of in-situ simulation for training in healthcare: opportunities and challenges.

Purpose of review: Simulation has now been acknowledged as an important part of training in healthcare, and most academic hospitals have a dedicated simulation center. In-situ simulation occurs in patient care units with scenarios involving healthcare professionals in their actual working environment. The purpose of this review is to describe the process of putting together the components of in-situ simulation for training programs and to review outcomes studied, and challenges with this approach. Recent findings: In-situ simulation has been used to 'test-drive' new centers, train personnel in new procedures in existing centers, for recertification training and to uncover latent threats in clinical care areas. It has also emerged as an attractive alternative to traditional simulations for institutions that do not have their own simulation center. Summary: In-situ simulation can be used to improve reliability and safety especially in areas of high risk, and in high-stress environments. It is also a reasonable and attractive alternative for programs that want to conduct interdisciplinary simulations for their trainees and faculty, and for those who do not have access to a fully functional simulation center. Further research needs to be done in assessing effectiveness of training using this method and the effect of such training on clinical outcomes. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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NonOperating Room Anesthesia: distancing from invasive surgery, embracing the era of interventional medicine.

No abstract available

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Recent advances of simulation in obstetric anesthesia.

Purpose of review: Simulation training in obstetric anesthesia has become widespread in recent years. Simulations are used to train staff and trainees, assess and improve team performance, and evaluate the work environment. This review summarizes current research in these categories. Recent findings: Simulation to improve individual technical skills has focused on induction of general anesthesia for emergent cesarean delivery, an infrequently encountered scenario by anesthesia trainees. Low- and high-fidelity simulation devices for the learning and practicing neuraxial and non-neuraxial procedures have been described, and both are equally effective. The use of checklists in obstetric emergencies has become common as and post-scenario debriefing techniques have improved. Although participant task performance improves, whether participants retain learned skills or whether simulation improves patient outcomes has not yet been established. Tools to assess teamwork during simulation have been developed, but none have been rigorously validated. In-situ vs. offsite simulations do not differ in effectiveness. Summary: Simulation allows for practice of tasks and teamwork in a controlled manner. There is little data whether simulation improves patient outcomes and metrics to predict the long-term retention of skills by simulation participants have not been developed. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Evaluation of fibroblast growth factor activity exerted by placental extract used as a cosmetic ingredient

Summary

Background

The biological activities claimed for placental extract (PE) in its medical and cosmetic applications are largely assumed to be the combined effects of its various signaling molecules and nutritional constituents. But there are considerable uncertainties about this assumption.

Aims

To determine the specific biological activity of PE at a molecular level.

Methods

Fibroblast growth factor (FGF) activity was assessed based on the ability to induce proliferation of FGF receptor (FGFR)-overexpressing BaF3 cells.

Results

Porcine PE (PPE), an ingredient in numerous cosmetics, activated proliferation of BaF3 cells overexpressing FGFR subtypes 1c, 2c, 2b, 3c, or 4, that is, all the major FGFR subtypes. The effect was suppressed largely or partially when the cells were treated with a FGFR inhibitor PD173074, and the FGFR-negative BaF3 parent cells exhibited minimal growth promotion as compared to the FGFR-expressing BaF3 cells. The high (>10 kDa) and low (<3 kDa) molecular weight fractions of PPE were effective activators of FGFR signaling. PPE was found to contain sulfated glycosaminoglycans, including heparin/heparan sulfate and chondroitin sulfate, which serve as both structural stabilizers of FGFs and indispensable cofactors for FGF-FGFR signaling.

Conclusions

These results indicate that PPE is capable of evoking FGF signaling in cells via FGFRs. Given that recombinant FGFs have proven useful for medical/cosmetic purposes, our results suggest that the medical/cosmetic utility of PPE is provided at least partly through the activation of FGF signaling in epidermal, dermal, and subdermal tissues.

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Novel immunologic mechanisms in eosinophilic esophagitis

Julie M Caldwell | Misu Paul | Marc E Rothenberg

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