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Focuses on identification of addiction manifested through drug-seeking behavior of patients with chronic pain who take opiate analgesics regularly. Phenomena that resembles addiction but are responses to unrelieved pain or anxiety; Means of ruling out pseudoaddiction; Signs of addiction; Cardinal characteristic of addiction.

Presents questions and answers related to the control of pain in patients. Questions a nurses method of not asking her patients what number reflects their pain; Difference between the use of a local anesthetic combination called TAC and a topical anesthetic mixture called LET; Response to questions. INSET: How to apply let..

Presents a question from a care giver asking how to calculate a rescue dose to reduce extreme pain in patients and should this rescue dose increase when the extended-release morphine does. Response to question.

Responds to an inquiry on pain management in sickle-cell disease. Medical interventions; Severity of pain; Follow-up care.

Presents answers to questions on pain management by nurses. Concerns about addiction to opioid analgesics; Pain indicators.

Focuses on the side effects of using opioid meperidine as a painkiller. Factors affecting the drug's half-life; Signs of neurotoxicity; Reduction of meperidine use.

Presents a question from a care giver asking about the use of extended release morphine products for one of her patients. Response to question.

Responds to an inquiry on pain management in postsurgical neonates. Concerns in nonventilated neonates; Use of analgesics; Nonpharmacologic interventions.

Gamma delta T (γδ T) cells are among the most potent cytotoxic lymphocytes. Activating anti–butyrophilin 3A (BTN3A) antibodies prime diverse tumor cell types to be killed by Vγ9Vδ2 T cells, the predominant γδ T cell subset in peripheral circulation, by mechanisms independent of tumor antigen–major histocompatibility complex (MHC) complexes. In this report, we describe the development of a humanized monoclonal antibody, ICT01, with subnanomolar affinity for the three isoforms of BTN3A. We demonstrate that ICT01-activated Vγ9Vδ2 T cells kill multiple tumor cell lines and primary tumor cells, but not normal healthy cells, in an efficient process requiring approximately 20% target occupancy. We show that ICT01 activity is dependent on BTN3A and BTN2A but independent of the phosphoantigen (pAg)–binding B30.2 domain. ICT01 delays the growth of hematologic and solid tumor xenografts and prolongs survival of NOD/SCID/IL2rγ null (NSG) mice adoptively transferred with human Vγ9Vδ2 T cells. In single- and multiple-dose safety studies in cynomolgus macaques that received up to 100 mg/kg once weekly, ICT01 was well tolerated. With respect to pharmacodynamic endpoints, ICT01 selectively activated Vγ9Vδ2 T cells without affecting other BTN3A-expressing lymphocytes such as αβ T or B cells. A first-in-human, phase 1/2a, open-label, clinical study of ICT01 was thus initiated in patients with advanced-stage solid tumors (EVICTION: NCT04243499; EudraCT: 2019-003847-31). Preliminary results show that ICT01 was well tolerated and pharmacodynamically active in the first patients. Digital pathology analysis of tumor biopsies of a patient with melanoma suggests that ICT01 may promote immune cell infiltration within the tumor microenvironment.

The anti-tumor response of Vγ9Vδ2 T cells requires the sensing of accumulated phosphoantigens (pAgs) bound intracellularly to butyrophilin 3A1 (BTN3A1). In this study, we show that butyrophilin 2A1 (BTN2A1) is required for BTN3A-mediated Vγ9Vδ2 T cell cytotoxicity against cancer cells, and that expression of the BTN2A1/BTN3A1 complex is sufficient to trigger Vγ9Vδ2 TCR activation. Also, BTN2A1 interacts with all isoforms of BTN3A (BTN3A1, BTN3A2, BTN3A3), which appears to be a rate-limiting factor to BTN2A1 export to the plasma membrane. BTN2A1/BTN3A1 interaction is enhanced by pAgs and, strikingly, B30.2 domains of both proteins are required for pAg responsiveness. BTN2A1 expression in cancer cells correlates with bisphosphonate-induced Vγ9Vδ2 T cell cytotoxicity. Vγ9Vδ2 T cell killing of cancer cells is modulated by anti-BTN2A1 monoclonal antibodies (mAbs), whose action relies on the inhibition of BTN2A1 binding to the Vγ9Vδ2TCR. This demonstrates the potential of BTN2A1 as a therapeutic target and adds to the emerging butyrophilin-family cooperation pathway in γδ T cell activation., Competing Interests: Declaration of interests D.O. is cofounder and shareholder of Imcheck Therapeutics. C.E.C., A.D.G., R.H., M.F., M.G., E.G., and C.K. are employees and shareholders of Imcheck Therapeutics. D.O. and C.P. are inventors of patent WO/2019/057933. The remaining authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Despite the powerful aspects of immune reactions, most often tumor cells are able to evade immune recognition and destruction. Cosignaling molecules from the B7/CD28 and TNF/TNFR superfamilies emerge as novel targets in immunotherapy. Upregulation of coinhibitory molecules by the tumor cells or tumor-infiltrating lymphocytes clearly attenuates T-cell responses against cancer and appears to be a mechanism exerted by the tumor to escape immune response. Today, a variety of coinhibitory molecules, including CTLA-4 and PD1 have been implicated in immune escape of cancer cells. Antagonist antibodies are developed to overcome immune evasion and until now anti-CTLA-4 and anti-PD1 antibodies have been tested in clinical trials with encouraging results. Here we summarize the recent advances made on PD1/PD1 ligands expression in cancer and we discuss about another couple of inhibitory molecules, BTLA and its ligand HVEM and their potential role in immune escape. Such information may provide novel therapeutic targets to reverse tumor-induced T-cell dysfunction in patients with advanced cancers., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The regulation of the immune system is controlled by many cell surface receptors. A prominent representative is the 'molecular switch' HVEM (herpes virus entry mediator) that can activate either proinflammatory or inhibitory signaling pathways. HVEM ligands belong to two distinct families: the TNF-related cytokines LIGHT and lymphotoxin-α, and the Ig-related membrane proteins BTLA and CD160. HVEM and its ligands have been involved in the pathogenesis of various autoimmune and inflammatory diseases, but recent reports indicate that this network may also be involved in tumor progression and resistance to immune response. Here we summarize the recent advances made regarding the knowledge on HVEM and its ligands in cancer cells, and their potential roles in tumor progression and escape to immune responses. Blockade or enhancement of these pathways may help improving cancer therapy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The TNF member LIGHT also known as TL4 or TNFSF14) can play a major role in cancer control via its two receptors; it induces tumor cell death through lymphotoxin-beta receptor (LT-betaR) and ligation to the herpes virus entry mediator (HVEM) amplifies the immune response. By studying the effect of LIGHT in the transcriptional profile of a lymphoid malignancy, we found that HVEM, but not LT-betaR, stimulation induces a significant increase in the expression of chemokine genes such as IL-8, and an unexpected upregulation of apoptotic genes. This had functional consequences, since LIGHT, or HVEM mAb, thus far known to costimulate T- and B-cell activation, induced chronic lymphocytic leukemia cell death. Many of the mediators involved were identified here, with an apoptotic pathway as demonstrated by caspases activation, decrease in mitochondrial membrane potential, upregulation of the pro-apoptotic protein Bax, but also a role of TRAIL. Moreover, HVEM induced endogenous TNF-alpha production and TNF-alpha enhanced HVEM-mediated cell death. HVEM function was mainly dependent on LIGHT, since other ligands like HSV-glycoprotein D and B and T lymphocyte attenuator were essentially ineffective. In conclusion, we describe a novel, as yet unknown killing effect of LIGHT through HVEM on a lymphoid malignancy, and combined with induction of chemokine release this may represent an additional tool to boost cancer immunotherapy.

In spite of recent advances in cancer therapy, some tumors still remain incurable and novel therapeutic approaches need to be developed. Apoptosis is a cell death inducing mechanism and is actually one of the most obvious targets for cancer treatment. It becomes clear that this regulation is more complex than previously expected, and multiple signalling pathways for cell death have to be considered. Agents with the property of inducing tumor cell death, such as TNF/TNFR superfamily members, also called "death receptors", represent an attractive therapeutic approach. Our team identified another member of this family, HVEM and its ligand LIGHT, as promising therapeutic targets. HVEM was known as a costimulatory molecule, but this role is getting more complex with the identification of new ligands and the highlights of new functions. So, HVEM could combine a pro-apoptotic effect with the immune system activation. This review will first focus on mechanisms and new insights in therapeutic application of TNF receptors. Then we will present new functions for LIGHT and HVEM and how these functions may provide new opportunities for antitumoral therapy and more effective treatments.