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Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolao

Medicine by Alexandros G.Sfakianakis

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Non-invasive diagnostic tools in the field of head and neck oncology : A liquid biopsy for head and neck cancers

The development of a liquid biopsy for head and neck cancers via  ScienceDirect Publication: Oral Oncology Publication ...

Τρίτη, 18 Οκτωβρίου 2016

Improving Treatment Options for Brain Metastases

s From ALK-Positive Non-Small-Cell Lung Cancer [EDITORIAL]:





Zabi Wardak and Hak Choy⇑

- Author Affiliations



University of Texas Southwestern Medical Center, Dallas, TX

Corresponding author: Hak Choy, MD, University of Texas Southwestern Medical Center, 5801 Forest Park Rd, Dallas, TX 75390; e-mail: hak.choy@utsouthwestern.edu.

Brain metastases occur in approximately 30% of patients with ALK-positive non–small-cell lung cancer (NSCLC), and in patients treated with crizotinib, CNS progression occurs in up to 70% of patients.1,2 Intracranial progression is believed to be a result of acquired resistance to crizotinib and inadequate penetration into the CNS.1 There are several options available for patients with brain metastases, including surgical resection, whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), or WBRT plus SRS. Recent randomized trials have shown that the addition of WBRT improves local and distant intracranial control compared with SRS alone; however, this comes at the cost of neurocognitive deterioration and decreased quality of life.3,4



Patients with brain metastases from ALK-positive NSCLC have a distinct natural history compared with patients with wild-type NSCLC. When treated with radiosurgery, the median survival for patients with brain metastases from wild-type NSCLC is 10 to 13 months,5,6 but in patients with ALK-positive NSCLC, the median survival has ranged from 27 to 50 months.7,8 Considering the neurocognitive decline with WBRT and the distinct natural history in patients with ALK-positive NSCLC with CNS metastases, efforts should be made to ensure appropriate disease control without compromising quality of life. Historically, radiosurgery had been limited to patients with four or fewer metastases; however, prospective inclusion of patients with five to 10 brain metastases has shown no difference in survival compared with patients treated with two to four metastases, coupled with excellent local control rates.6 Advancements in radiosurgery with the Gamma Knife (Elekta, Stockholm, Sweden) have shown the ability to treat multiple brain metastases with limited normal brain irradiation, expanding the eligibility for patients with brain metastases beyond historical inclusion criteria.9,10 This provides an attractive option for intracranial control for patients with ALK-positive NSCLC.



In the phase I dose-finding study of alectinib in patients with crizotinib-resistant ALK-positive NSCLC, 52% of patients with CNS disease had an objective response with measurable concentrations of alectinib found in CSF samples, demonstrating promising intracranial activity with alectinib.11 This prompted two phase II trials evaluating alectinib in patients with crizotinib-refractory ALK-positive NSCLC.12,13 Gadgeel et al11 have pooled data from the two phase II trials with focus on the intracranial response with alectinib. Sixty percent of the pooled patient population (n = 136) presented with baseline CNS disease before initiation of alectinib, with the majority receiving prior CNS radiotherapy greater than 6 months before starting alectinib. Acceptable prior CNS radiotherapy included WBRT or SRS. With a median follow-up time of 12 months, two thirds of patients with measurable CNS disease had an objective response.



Alectinib successfully achieved two goals. First, it resulted in measurable extracranial response in patients with progression on crizotinib, and second, it showed measurable activity in the CNS. A large percentage of patients had a remote (> 6 months) history of CNS-directed radiotherapy, suggesting that the CNS response rates can be attributed to alectinib. Furthermore, treatment with alectinib shows a promising shift in the site of progression of disease in patients with ALK-positive NSCLC. The rates of CNS progression were as high as 70% with first-line crizotinib, yet across all patients in the two trials, CNS progression occurred in only 17% of the combined study population and as the sole site of progression in 11%. The results were even more promising in patients who did not have baseline CNS disease; only 8% of those patients ultimately went on to develop CNS progression.



With the introduction of alectinib, unique new scenarios for patients and clinicians will arise in the setting of ALK-positive CNS metastases. Each patient will require careful consideration, and all oncologic disciplines should be included in the discussion of each patient with CNS metastases so as to determine each individual patient’s optimal treatment course. Patients with symptomatic CNS disease were ineligible for these trials and require urgent treatment with either surgery or radiotherapy, which should take precedence. In asymptomatic patients, multiple scenarios may arise. With first-line crizotinib therapy, a patient may have controlled systemic disease with asymptomatic intracranial progression. With the neurocognitive adverse effects shown with the addition of WBRT to SRS in two randomized phase III trials,3,4 WBRT could be spared and patients could be considered for intervention with SRS, because it can be delivered without compromising the patient’s quality of life, with limited toxicity, and without a break in systemic therapy. This would allow continuation of crizotinib in hopes of extracting maximal extracranial control. If there is further intracranial progression, then repeat SRS could be performed. If a patient is ineligible for SRS, then consideration of transition to alectinib in hopes of avoiding WBRT may be considered.



For patients who have both systemic and intracranial progression on crizotinib and remain asymptomatic, switching to alectinib with close monitoring of the CNS for treatment response, with intervention with SRS if there are nonresponding lesions, may be an option. However, this highlights one of the limitations of the pooled analysis, in that the extent of intracranial disease (size and volume) was not presented. We do not know how well alectinib works regarding control of larger metastases because these are more likely to become symptomatic. It may be prudent to intervene early with SRS in hopes of providing the best opportunity for tumor control, because even with radiosurgery, tumor control declines with increasing tumor size.14



For patients for whom observation is chosen, it is important in continued follow-up that the imaging technique is consistent and appropriate for sensitivity in detection of intracranial disease so that response criteria can be accurately assessed longitudinally. Almost two thirds of patients in the pooled analysis had a component of nonmeasurable disease, indicating that ALK-positive CNS metastases frequently have smaller metastases that require a careful imaging technique, with slice thickness, contrast dosing, and magnetic resonance field strength all potential factors in the detection of CNS metastatic disease.15-17 Furthermore, 28% of the patient population underwent CT-based imaging, and when compared with MRI, it is less sensitive for the detection of brain metastases and may underestimate the extent of disease.18,19



These are encouraging results for patients and practitioners in the treatment of CNS metastases from ALK-positive NSCLC, with both drug and radiosurgery treatment options available that can maintain quality of life and prevent disease progression. Currently, crizotinib is first-line therapy for ALK-positive NSCLC; however, two randomized trials are comparing alectinib versus crizotinib in the first-line setting (ALEX/J-ALEX), with early results showing promising results in favor of alectinib.20 If alectinib becomes first-line therapy, the ideal way to determine how to treat asymptomatic brain metastases on presentation could best be answered with a trial comparing up-front radiosurgery plus alectinib versus alectinib alone, with careful attention to the extent of intracranial disease in the two arms, because subsets of patients may derive maximum benefit from combined therapy, for example, for larger metastases. Ultimately, it may be that a combination of the two provides the best solution, with radiosurgery providing excellent local control of treated lesions that, when followed by alectinib, may be further improved while simultaneously providing distant intracranial control, synonymous with SRS plus WBRT, without the neurocognitive toxicity and with maintenance of quality of life.





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AUTHOR CONTRIBUTIONS



Administrative support: Hak Choy



Manuscript writing: All authors



Final approval of manuscript: All authors



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AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST



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Improving Treatment Options for Brain Metastases From ALK-Positive Non–Small-Cell Lung Cancer

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.



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Zabi Wardak

No relationship to disclose



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Hak Choy

Stock or Other Ownership: Texas Radiotherapy Innovation and Optimization



Consulting or Advisory Role: Vertex, Genentech, Celgene



Research Funding: Celgene (Inst)



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Footnotes



See accompanying article doi:10.1200/JCO.2016.68.4639

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REFERENCES



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Related Article

ORIGINAL REPORTS - Clinical Trials:

Pooled Analysis of CNS Response to Alectinib in Two Studies of Pretreated Patients With ALK-Positive Non–Small-Cell Lung Cancer

Shirish M. Gadgeel, Alice T. Shaw, Ramaswamy Govindan, Leena Gandhi, Mark A. Socinski, D. Ross Camidge, Luigi De Petris, Dong-Wan Kim, Alberto Chiappori, Denis L. Moro-Sibilot, Michael Duruisseaux, Lucio Crino, Tommaso De Pas, Eric Dansin, Antje Tessmer, James Chih-Hsin Yang, Ji-Youn Han, Walter Bordogna, Sophie Golding, Ali Zeaiter, and Sai-Hong Ignatius Ou

JCO JCO684639; published online on October 3, 2016;

[Abstract] [Full Text] [PDF]



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Slideshows

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Tinnitus

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2. Akdogan O, Ozcan I, Ozbek C, Dere H. Tinnitus after cochlear implantation. Auris Nasus Larynx. 2009;36:210-212. [abstract]

3. Pan T, Tyler RS, Ji H, Coelho C, Gehringer AK, Gogel SA. Changes in the tinnitus handicap questionnaire after cochlear implantation. American Journal of Audiology. 2009;18:144-151. [abstract]

4. Andersson G, Freijd A, Baguley DM, Idrizbegovic E. Tinnitus distress, anxiety, depression, and hearing problems among cochlear implant patients with tinnitus. Journal of the American Academy of Audiology. 2009;20:315-319. [abstract]

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6. Di NW, Cianfrone F, Scorpecci A, Cantore I, Giannantonio S, Paludetti G. Transtympanic electrical stimulation for immediate and long-term tinnitus suppression. International Tinnitus Journal. 2009;15:100-106.[abstract]

7. Litre CF, Theret E, Tran H et al. Surgical treatment by electrical stimulation of the auditory cortex for intractable tinnitus. Brain Stimulation. 2009;2:132-137. [abstract]

8. Evans RW, Ishiyama G. Migraine with transient unilateral hearing loss and tinnitus. Headache: The Journal of Head & Face Pain. 2009;49:756-759. [abstract]

9. Pirodda A, Brandolini C, Raimondi MC, Ferri GG, Borghi C. Tinnitus as a warning for preventing vasovagal syncope. Medical Hypotheses. 2009;73:370-371. [abstract]

10. Anderson JE, Teitel D, Wu YW. Venous hum causing tinnitus: case report and review of the literature. Clinical Pediatrics. 2009;48:87-89. [abstract]

11. Liess BD, Lollar KW, Christiansen SG, Vaslow D. Pulsatile tinnitus: a harbinger of a greater ill? Head & Neck. 2009;31:269-273. [abstract]

12. Singh DP, Forte AJ, Brewer MB, Nowygrod R. Bilateral carotid endarterectomy as treatment of vascular pulsatile tinnitus. Journal of Vascular Surgery. 2009;50:183-185. [abstract]

13. Delgado F, Munoz F, Bravo-Rodriguez F, Jurado-Ramos A, Oteros R. Treatment of dural arteriovenous fistulas presenting as pulsatile tinnitus. Otology and Neurotology. 2009;30:897-902. [abstract]

14. Cowley PO, Jones R, Tuch P, McAuliffe W. Pulsatile tinnitus from reversal of flow in an aberrant occipital artery: Resolved after carotid artery stenting. American Journal of Neuroradiology. 2009;30:995-997. [abstract]

15. Stimmer H, Borrmann A, Loer C, Arnold W, Rummeny EJ. Monaural tinnitus from a contralateral inferior colliculus hemorrhage. Audiology & Neurotology. 2009;14:35-38. [abstract]

16. Latifpour DH, Grenner J, Sjodahl C. The effect of a new treatment based on somatosensory stimulation in a group of patients with somatically related tinnitus. International Tinnitus Journal. 2009;15:94-99. [abstract]

17. Department of Health. Provision of services for adults with tinnitus: a good practice guide. 2009. [full text]

18. DH. Tinnitus Map of Medicine care pathway. 2010. [Full text]

19. BTA. Tinnitus: guidelines for primary care. 2010. [Full text]

20. Schneider P, Andermann M, Wengenroth M et al. Reduced volume of Heschl's gyrus in tinnitus. NeuroImage. 2009;45:927-939. [abstract]

21. Landgrebe M, Langguth B, Rosengarth K et al. Structural brain changes in tinnitus: grey matter decrease in auditory and non-auditory brain areas. NeuroImage. 2009;46:213-218. [abstract]

22. Melcher JR, Levine RA, Bergevin C, Norris B. The auditory midbrain of people with tinnitus: Abnormal sound-evoked activity revisited. Hearing Research. 2009;257:63-74. [abstract]

23. Lanting CP, de KE, van DP. Neural activity underlying tinnitus generation: Results from PET and fMRI. Hearing Research. 2009;255:1-13. [abstract]

24. Kaltenbach JA. Insights on the origins of tinnitus: an overview of recent research. Hearing Journal. 2009;62:26-31. [Full text]

25. Shulman A, Goldstein B, Strashun AM. Final common pathway for tinnitus: theoretical and clinical implications of neuroanatomical substrates. International Tinnitus Journal. 2009;15:5-50. [abstract]

26. Schutte NS, Noble W, Malouff JM, Bhullar N. Evaluation of a model of distress related to tinnitus. International Journal of Audiology. 2009;48:428-432. [abstract]

27. Hesser H, Pereswetoff-Morath CE, Andersson G. Consequences of controlling background sounds: the effect of experiential avoidance on tinnitus interference. Rehabilitation Psychology. 2009;54:381-390.[abstract]

28. Argstatter H, Krick C, Bolay HV. Music therapy for chronic tinnitus. Heidelberg treatment model. Psychotherapeut. 2009;54:17-26. [abstract]

29. Lugli M, Romani R, Ponzi S, Bacciu S, Parmigiani S. The windowed sound therapy: A new empirical approach for an effective personalized treatment of tinnitus. International Tinnitus Journal. 2009;15:51-61.[abstract]

30. Langguth B, Salvi R, Elgoyhen AB. Emerging pharmacotherapy of tinnitus. Expert Opinion on Emerging Drugs. 2009;14:687-702. [abstract]

31. Campbell KCM. Emerging pharmacologic treatments for hearing loss and tinnitus. ASHA Leader. 2009;14:14-18. [Full text]

32. Hesser H, Westin V, Hayes SC, Andersson G. Clients' in-session acceptance and cognitive defusion behaviors in acceptance-based treatment of tinnitus distress. Behaviour Research & Therapy. 2009;47:523-528. [abstract]

33. Hesser H, Andersson G. The role of anxiety sensitivity and behavioral avoidance in tinnitus disability. International Journal of Audiology. 2009;48:295-299. [abstract]

34. Shulman A, Goldstein B. Subjective idiopathic tinnitus and palliative care: a plan for diagnosis and treatment. Otolaryngologic Clinics of North America. 2009;42:15-38. [abstract]

35. Forti S, Costanzo S, Crocetti A, Pignataro L, Del BL, Ambrosetti U. Are results of tinnitus retraining therapy maintained over time? 18-month follow-up after completion of therapy. Audiology & Neuro-Otology. 2009;14:286-289. [abstract]

36. Bessman P, Heider T, Watten VP, Watten RG. The tinnitus intensive therapy habituation program: a 2-year follow-up pilot study on subjective tinnitus. Rehabilitation Psychology. 2009;54:133-138. [abstract]

37. Gudex C, Skellgaard PH, West T, Sorensen J. Effectiveness of a tinnitus management programme: A 2-year follow-up study. BMC Ear, Nose and Throat Disorders. 2009;9. [Full text]

38. Henry J, Zaugg T, Myers P, Kendall C, Turbin M. Principles and application of educational counseling used in progressive audiologic tinnitus management. Noise and Health. 2009;11:33-48. [abstract]

1. Hazell JW, Jastreboff PJ. Tinnitus. I: Auditory mechanisms: a model for tinnitus and hearing impairment. J Otolaryngol. 1990;19:1-5. [Abstract]

2. Jastreboff PJ, Jastreboff MM. Tinnitus Retraining Therapy (TRT) as a method for treatment of tinnitus and hyperacusis patients. J Am Acad Audiol. 2000 Mar;11(3):162-77. [Abstract]

3. Marcondes RA, Sanchez TG, Kii MA, Langguth et al. Repetitive transcranial magnetic stimulation improve tinnitus in normal hearing patients: a double-blind controlled, clinical and neuroimaging outcome study. Eur J Neurol. 2009. [Epub ahead of print] ) [Abstract]

4. Cannon SC Pathomechanisms in channelopathies of skeletal muscle and brain. Annu Rev Neurosci. 2006;29:387-415. [Abstract]

5. Davies E, Knox E, Donaldson I. The usefulness of nimodipine, an L-calcium channel antagonist, in the treatment of tinnitus. Br J Audiol. 1994;28:125-129. [Abstract]

6. Baguley DM, Jones S, Wilkins I, Axon PR, Moffat DA. The inhibitory effect of intravenous lidocaine infusion on tinnitus after translabyrinthine removal of vestibular schwannoma: a double-blind, placebo-controlled, crossover study. Otol Neurotol. 2005;26:169-176. [Abstract]

Eggermont JJ. Cortical tonotopic map reorganization and its implications for treatment of tinnitus. Acta Otolaryngol Suppl. 2006;9-12. [Abstract]

Hoke ES, Muhlnickel W, Ross B, Hoke M. Tinnitus and event-related activity of the auditory cortex. Audiol Neurootol. 1998;3:300-331. [Abstract]

Mirz F, Pedersen B, Ishizu K et al. Positron emission tomography of cortical centers of tinnitus. Hear Res. 1999;134:133-144. [Abstract]

Muhlnickel W, Elbert T, Taub E, Flor H. Reorganization of auditory cortex in tinnitus. Proc Natl Acad Sci U S A. 1998;95:10340-10343. [Abstract]

Norena AJ, Eggermont JJ. Enriched acoustic environment after noise trauma abolishes neural signs of tinnitus. Neuroreport. 2006;17:559-563. [Abstract]

Schlee W, Hartmann T, Langguth B, Weisz N. Abnormal resting-state cortical coupling in chronic tinnitus. BMC Neurosci. 2009;10:11. [Full text]

Schlee W, Mueller N, Hartmann T, Keil J, Lorenz I, Weisz N. Mapping cortical hubs in tinnitus. BMC Biol. 2009;7:80. [Full text]

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HIPPOCRATE'S OATH

"I swear by Apollo, the healer, Asclepius, Hygieia, and Panacea, and I take to witness all the gods, all the goddesses, to keep according to my ability and my judgment, the following Oath and agreement:

To consider dear to me, as my parents, him who taught me this art; to live in common with him and, if necessary, to share my goods with him; To look upon his children as my own brothers, to teach them this art.

I will prescribe regimens for the good of my patients according to my ability and my judgment and never do harm to anyone.

I will not give a lethal drug to anyone if I am asked, nor will I advise such a plan; and similarly I will not give a woman a pessaryto cause an abortion.

But I will preserve the purity of my life and my arts.

I will not cut for stone, even for patients in whom the disease is manifest; I will leave this operation to be performed by practitioners, specialists in this art.

In every house where I come I will enter only for the good of my patients, keeping myself far from all intentional ill-doing and all seduction and especially from the pleasures of love with women or with men, be they free or slaves.

All that may come to my knowledge in the exercise of my profession or in daily commerce with men, which ought not to be spread abroad, I will keep secret and will never reveal.

If I keep this oath faithfully, may I enjoy my life and practice my art, respected by all men and in all times; but if I swerve from it or violate it, may the reverse be my lot."

MAIMONIDE'S PRAYER

"Almighty God, Thou has created the human body with infinite wisdom. Ten thousand times ten thousand organs hast Thou combined in it that act unceasingly and harmoniously to preserve the whole in all its beauty the body which is the envelope of the immortal soul. They are ever acting in perfect order, agreement and accord. Yet, when the frailty of matter or the unbridling of passions deranges this order or interrupts this accord, then forces clash and the body crumbles into the primal dust from which it came. Thou sendest to man diseases as beneficent messengers to foretell approaching danger and to urge him to avert it.

"Thou has blest Thine earth, Thy rivers and Thy mountains with healing substances; they enable Thy creatures to alleviate their sufferings and to heal their illnesses. Thou hast endowed man with the wisdom to relieve the suffering of his brother, to recognize his disorders, to extract the healing substances, to discover their powers and to prepare and to apply them to suit every ill. In Thine Eternal Providence Thou hast chosen me to watch over the life and health of Thy creatures. I am now about to apply myself to the duties of my profession. Support me, Almighty God, in these great labors that they may benefit mankind, for without Thy help not even the least thing will succeed.

"Inspire me with love for my art and for Thy creatures. Do not allow thirst for profit, ambition for renown and admiration, to interfere with my profession, for these are the enemies of truth and of love for mankind and they can lead astray in the great task of attending to the welfare of Thy creatures. Preserve the strength of my body and of my soul that they ever be ready to cheerfully help and support rich and poor, good and bad, enemy as well as friend. In the sufferer let me see only the human being. Illumine my mind that it recognize what presents itself and that it may comprehend what is absent or hidden. Let it not fail to see what is visible, but do not permit it to arrogate to itself the power to see what cannot be seen, for delicate and indefinite are the bounds of the great art of caring for the lives and health of Thy creatures. Let me never be absent- minded. May no strange thoughts divert my attention at the bedside of the sick, or disturb my mind in its silent labors, for great and sacred are the thoughtful deliberations required to preserve the lives and health of Thy creatures.

"Grant that my patients have confidence in me and my art and follow my directions and my counsel. Remove from their midst all charlatans and the whole host of officious relatives and know-all nurses, cruel people who arrogantly frustrate the wisest purposes of our art and often lead Thy creatures to their death.

"Should those who are wiser than I wish to improve and instruct me, let my soul gratefully follow their guidance; for vast is the extent of our art. Should conceited fools, however, censure me, then let love for my profession steel me against them, so that I remain steadfast without regard for age, for reputation, or for honor, because surrender would bring to Thy creatures sickness and death.

"Imbue my soul with gentleness and calmness when older colleagues, proud of their age, wish to displace me or to scorn me or disdainfully to teach me. May even this be of advantage to me, for they know many things of which I am ignorant, but let not their arrogance give me pain. For they are old and old age is not master of the passions. I also hope to attain old age upon this earth, before Thee, Almighty God!

"Let me be contented in everything except in the great science of my profession. Never allow the thought to arise in me that I have attained to sufficient knowledge, but vouchsafe to me the strength, the leisure and the ambition ever to extend my knowledge. For art is great, but the mind of man is ever expanding.

"Almighty God! Thou hast chosen me in Thy mercy to watch over the life and death of Thy creatures. I now apply myself to my profession. Support me in this great task so that it may benefit mankind, for without Thy help not even the least thing will succeed."

Information for Health Professionals

Information for Patients

Modern challenged parts of the oath:

  1. To teach medicine to the sons of my teacher. In the past, medical schools gave preferential consideration to the children of physicians.
  2. To practice and prescribe to the best of my ability for the good of my patients, and to try to avoid harming them. This beneficial intention is the purpose of the physician. However, this item is still invoked in the modern discussions of euthanasia.
  3. I will not give a lethal drug to anyone if I am asked, nor will I advise such a plan. Physician organizations in most countries have strongly denounced physician participation in legal executions. However, in a small number of cases, most notably the U.S. states of Oregon,[10] Washington,[11]Montana,[12] and in the Kingdom of the Netherlands,[13] a doctor can prescribe euthanasia with the patient's consent.
  4. Similarly, I will not give a woman a pessary to cause an abortion. Since the legalization of abortion in many countries, the inclusion of the anti-abortion sentence of the Hippocratic oath has been a source of contention.
  5. To avoid violating the morals of my community. Many licensing agencies will revoke a physician's license for offending the morals of the community ("moral turpitude").
  6. I will not cut for stone, even for patients in whom the disease is manifest; I will leave this operation to be performed by practitioners, specialists in this art. The "stones" referred to are kidney stones or bladder stones, removal of which was judged too menial for physicians, and therefore was left for barbers (the forerunners of modern surgeons). Surgery was not recognized as a specialty at that time. This sentence is now interpreted as acknowledging that it is impossible for any single physician to maintain expertise in all areas. It also highlights the different historical origins of the surgeon and the physician.
  7. To keep the good of the patient as the highest priority. There may be other conflicting 'good purposes,' such as community welfare, conserving economic resources, supporting the criminal justice system, or simply making money for the physician or his employer that provide recurring challenges to physicians
http://www.worldallergy.org/educational_programs/world_allergy_forum/barcelona2008/rabe/

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