Targeting cells of the myeloid lineage attenuates pain and disease progression in a prostate model of bone cancer.

Thompson, Michelle L.; Jimenez-Andrade, Juan Miguel; Chartier, Stephane; Tsai, James; Burton, Elizabeth A.; Habets, Gaston; Lin, Paul S.; West, Brian L.; Mantyh, Patrick W.

Published Ahead-of-Print

Abstract

Tumor cells frequently metastasize to bone where they can generate cancer-induced bone pain (CIBP) that can be difficult to fully control using available therapies. Here we explored whether PLX3397, a high affinity, small molecular antagonist that binds to and inhibits phosphorylation of colony stimulating factor-1 receptor (CSF1R), the tyrosine-protein kinase c-Kit, and the FMS-like tyrosine kinase 3 (FLT3), can reduce CIBP.

These three targets all regulate the proliferation and function of a subset of the myeloid cells including macrophages, osteoclasts, and mast cells. Preliminary experiments show that PLX3397 attenuated inflammatory pain following formalin injection into the hindpaw of the rat.

 As there is an inflammatory component in CIBP, involving macrophages and osteoclasts, the effect of PLX3397 was explored in a prostate model of CIBP where skeletal pain, cancer cell proliferation, tumor metastasis, and bone remodeling could be monitored in the same animal. 

Administration of PLX3397 was initiated on day 14 following prostate cancer cell injection when the tumor was well established and tumor-induced bone remodeling was first evident. 

Over the next six weeks, sustained administration of PLX3397 attenuated CIBP behaviors by approximately 50% and was equally efficacious in reducing tumor cell growth, formation of new tumor colonies in bone, and pathological tumor-induced bone remodeling.

 Developing a better understanding of potential effects analgesic therapies have on the tumor itself may allow the development of therapies which not only better control the pain but positively impact disease progression and overall survival in patients with bone cancer.

(C) 2015 International Association for the Study of Pain

J Clin Oncol. 2014 Jun 1;32(16):1671-6.

New opioids.

Mercadante S1, Porzio G2, Gebbia V2.

Author information

Abstract

Despite the skilled use of opioid analgesics, which is crucial to the relief of cancer pain, there is a lack of evidence to support many aspects of current clinical practice. 

Therefore, there is a significant need for more effective treatment options.

 New opioids have been marketed in the past years, including hydrocodone and oxymorphone.

 Moreover, mixed opioids with combined mechanisms of action have been developed; one such agent, tapentadol, is a centrally acting oral analgesic that possesses a combined mechanism of action: μ-opioid receptor activation with norepinephrine reuptake inhibition. Drug development strategies involving naloxone have been initiated to reduce peripheral opioid-related adverse effects.

 The rationale is based on the local antagonist activity of naloxone in intestinal opioid receptors and the negligible oral bioavailability of naloxone, particularly in a prolonged-release formulation. New delivery systems have been developed to provide rapid analgesia with potent opioid drugs such as fentanyl.

 Despite the upcoming availability of these new drugs and technologies that will add to existing types of opioid medication, their benefits and liabilities will ultimately need to be determined by the individual physician and individual patient experiencing pain.

© 2014 by American Society of Clinical Oncology.

Schmerz. 2015 Apr;29(2):211-6

[Euthanasia and physician-assisted suicide : Attitudes of physicians and nurses].

[Article in German]

Zenz J1, Tryba M, Zenz M.

Author information

Abstract

BACKGROUND:

The current debate about end-of-life decisions in Germany focuses on physician-assisted suicide (PAS). However, there is only limited information available on physicians' attitudes towards euthanasia or PAS, and no data on nurses' attitudes.

OBJECTIVES:

The aim is to explore attitudes of physicians and nurses with a special interest in palliative care and pain medicine using a case-related questionnaire.

METHODS:

An anonymous questionnaire, consisting of eight questions, was distributed to all participants of a palliative care congress and a painsymposium. The questions focused on two scenarios: (1) a patient with an incurable fatal illness, (2) a patient with an incurable but nonfatal illness. 

The question was: Should euthanasia or physician-assisted suicide (PAS) be allowed. In addition, the participants were asked what they wanted for themselves if they were the patient concerned.

RESULTS:

A total of 317 questionnaires were analyzed; the return rate was 70 %. The general support for euthanasia and PAS was high: 40.5 % supported euthanasia in case of a fatal illness ("definitely…", "probably should be allowed"), 53.5 % supported PAS. 

The support decreased in case of a nonfatal illness; however, it increased when the participants were asked about their attitudes if they were the patient concerned. Nurses were more open towards euthanasia and PAS. In physicians the rejection of PAS was directly related to a higher level of qualification in the field ofpalliative care.

CONCLUSION:

The fact that nurses had a more positive attitude towards euthanasia and PAS and that all respondents accepted life-ending acts for themselves more than for their patients hints to still existing severe deficits in Germany.

Arch Kriminol. 2013 Mar-Apr;231(3-4):73-115.

[Legal issues of physician-assisted euthanasia. Part III--Passive euthanasia, comparison of international legislation, conclusions for medical practice].

[Article in German]

Laux J1, Röbel A, Parzeller M.

Author information

Abstract

The generic term "passive euthanasia" includes different issues dealing with the omission, discontinuation or termination of life-sustaining or life-prolonging medical treatments. The debate around passive euthanasia focuses on the constitutional right of self-determination of every human being on the one hand and the constitutional mandate of the State to protect human life on the other. Issues of passive euthanasia always require a differentiated approach. Essentially, it comes down to the following: In Germany, the human right of self-determination includes the right to prohibit the performance of life-sustaining treatments, even if this leads to the death of the patient. A physician who does not take life-sustaining treatment measures because this is the free will expressed by the patient is not subject to prosecution. On the other hand, if the physician treats the patient against his will, this can be deemed a punishable act of bodily injury. The patient's will is decisive even if his concrete state of health does no longer allow him to freely express his will. In the Patient's Living Will Act of 2009, the German legislator clarified the juridical assessment of such constellations being of particular relevance in practice.

 A written living will of a person in which he requests to take or not to take certain medical treatment measures in case that he is no longer able to make the decision himself shall be binding for the people involved in the process of medical treatment. If there is no living will, the supposed will of the patient shall be relevant. In its judgment in the "Putz case", the German Federal Court of Justice ruled in 2010 that actions terminating a life-sustaining treatment that does not correspond to the patient's will must be limited to letting an already ongoing disease process run its course. In this context it is not important, however, whether treatment is discontinued by an active act or by omission. Under certain circumstances, the termination of life-sustaining measures can also be permitted if they are no longer medically indicated. Looking to other European countries and the USA it becomes evident that euthanasia is the subject of controversial discussion and interpretation not only in Germany.

Arch Kriminol. 2013 Jan-Feb;231(1-2):1-37.

[Legal issues of physician-assisted euthanasia. Part II--Help in the dying process, direct and indirect active euthanasia].

[Article in German]

Laux J1, Röbel A, Parzeller M.

Author information

Abstract

In Germany, physician-assisted euthanasia involves numerous risks for the attending physician under criminal and professional law. In the absence of clear legal provisions, four different categories of euthanasia have been developed in legal practice and the relevant literature: help in the dying process, direct active euthanasia, indirect active euthanasia and passive euthanasia. The so-called "help during the dying process" by administering medically indicated analgesic drugs without a life-shortening effect is exempt from punishment if it corresponds to the will of the patient. If the physician omits to give such analgesic drugs although the patient demands them, this is deemed a punishable act of bodily injury. The same applies if the physician administers analgesics against the will of the patient. Medically indicated pain treatment which has a potential or certain life-shortening effect (indirect active euthanasia) is permitted under certain conditions: if there are no alternative and equally suitable treatment options without the risk of shortening the patient's life, if the patient has given his consent to the treatment and if the physician does not act with the intention to kill. 

The deliberate killing of a dying or terminally ill patient for the purpose of ending his suffering (direct active euthanasia) is prohibited. This includes both deliberately killing a patient against or without his will (by so-called "angels of death") and the killing of a patient who expressly and earnestly demands such an act from his physician (killing on request/on demand). Physician-assisted suicide is generally not liable to punishment in Germany. Nevertheless, the action may be subject to punishment if the physician omits to rescue the life of an unconscious suicide victim. "Palliative sedation" is regarded as a special case. It may become necessary if certain symptoms in the terminal stage of a fatal disease unbearable for the patient cannot be controlled by any other means. The legal assessment of "palliative sedation" depends on the circumstances of the individual case, in particular the "informed consent" of the patient and the physician's intention.