Winter 2014 – Vemurafenib: Background, Patterns of Resistance, and Strategies to Combat Resistance in Melanoma

Vemurafenib: Background, Patterns of Resistance, and Strategies to Combat Resistance in Melanoma.
Arjun Dupati* and Liza Gill
Author Affiliations:
College of Human Medicine, Michigan State University, East Lansing, MI, USA


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*Corresponding author: Arjun Dupati; dupatiar[at]
Arjun Dupati and Liza Gill contributed equally to the production of this manuscript.
Key Words: Vemurafenib; Molecular Targeted Therapy; Melanoma Drug Resistance; Metastatic Melanoma; Tyrosine Kinase Inhibitor; Melanoma Treatment.
Introduction: Finding an effective treatment for metastatic melanoma has posed a series of challenges. Vemurafenib, a B-RAF tyrosine kinase inhibitor, has been one of the most successful medications to date in the treatment of metastatic melanoma. B-RAF is a serine/threonine kinase that is a part of the RAS-RAF-MEK-ERK signal transduction pathway, which plays a pivotal role in cellular proliferation, differentiation, and survival. Mutations in the B-RAF protein lead to a deregulated activation of MAPK and ERK.
The focus of this review article is resulting resistance to vemurafenib and its clinical implications on the treatment of metastatic melanoma. This paper aims to highlight mechanisms of vemurafenib resistance that have been observed so far and offer potential clinical approaches to overcome resistance.
Methods: PubMed, Google Scholar, and EMBASE were searched using the following free text terms: “vemurafenib,” “vemurafenib resistance,” “vemurafenib tyrosine-kinase inhibitor,” “vemurafenib metastatic melanoma,” “vemurafenib alternatives,” and “vemurafenib cancer.” The Cochrane database was searched for randomized controlled trials and systematic reviews using the same search terms above. Two independent reviewers analyzed the search results and corresponding articles.
Discussion: Research over the last decade, most notably in the past two years has revealed a multitude of mechanisms of resistance to vemurafenib. Resistance to therapy with vemurafenib in metastatic melanoma could be explained by the presence of cancer stem cells.
Conclusion: In order to effectively circumvent resistance, it would behoove clinicians to approach metastatic melanoma with a cocktail of inhibitors as opposed to monotherapy.

Published: January 1, 2014
Senior Editor: Kailyne Van Stavern
Junior Editor: Kaitlyn Vitale
DOI: Pending
Dupati A, Gill L. Vemurafenib: Background, Patterns of Resistance, and Strategies to Combat Resistance in Melanoma. Medical Student Research Journal. 2014;3(Winter):36-43.
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Winter 2014 – Substance Use Among Physicians and Medical Students

Substance Use Among Physicians and Medical Students.
Catalina I. Dumitrascu1*, Philip Z. Mannes2, Lena J. Gamble3, Jeffrey A. Selzer4
Author Affiliations:
1Creighton University School of Medicine, Omaha, NE, USA.
2Dartmouth College, Hanover, NH, USA.
3National Institutes of Health, Department of Perioperative Medicine, Bethesda, MD, USA.
4Committee for Physician Health, Albany, NY, USA.

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Corresponding author: Catalina I. Dumitrascu, BS, MS; catalinadumitrascu[at]

Key Words: Substance-related disorders; Alcohol abuse; Physician Health Programs.
Background: Physicians and medical students whose substance use causes impairment pose a risk to both themselves and their patients. Drug abuse is a documented problem in physicians, however few studies have investigated the rates of drug abuse in medical students. While treatment plans may be tailored for both students and attending physicians, there is often a reluctance to refer one’s self or a colleague due to a variety of reasons related to fear of repercussions, belief the problem has already been addressed, failure to recognize, or ignorance. This review provides a brief background on common signs and symptoms of potential abuse and resources available to doctors in training at various stages of their career, along with providing a clear picture of the literature as it pertains to physician and medical student substance abuse.
Methods: Extensive search of the literature utilized physical and electronic resources available at the National Institutes of Health Library and the National Library of Medicine with search results limited to the topics of physician or medical student substance use, substance abuse, impairment, and treatment.
Results: Sparse recent data regarding physician and medical student substance abuse are available. Studies completed two decades ago demonstrate that drug abuse was a significant problem for doctors and medical students at that time.
Conclusion: Due to outdated, and/or incomplete data on substance abuse in physicians and especially medical students, it is difficult to report the current extent of substance abuse in these groups. Nonetheless, it is important to recognize substance abuse in these populations and promote referral to substance abuse programs. Early rehabilitation and treatment improves both career and patient outcomes. This study highly suggests the need for up to date information regarding substance abuse in the medical community so that appropriate resources can be developed and effectively utilized.

Published: January 1, 2014
Senior Editor: Kevin C. Patterson
Junior Editor: Caela Hesano
DOI: Pending
Dumitrascu CI, Mannes PZ, Gamble LJ, Selzer JA. Substance Use Among Physicians and Medical Students. Medical Student Research Journal. 2014;3(Winter):26-35.
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Winter 2014 – Morphine-induced Myoclonus in a Patient with End-stage Renal Disease

Morphine-Induced Myoclonus in a Patient with End-Stage Renal Disease.
Victoria L. Stahl1*, Hassan I. Ahmad2, and James E. Novak3
Author Affiliations:
1School of Medicine, Wayne State University, Detroit, MI, USA.
2Department of Medicine, Henry Ford Hospital, Detroit, MI, USA.
3Division of Nephrology and Hypertension, Henry Ford Hospital, Detroit, MI, USA.


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*Corresponding author: Victoria Stahl, BS; vstahl[at]

Key Words: End-Stage Renal Disease; Dialysis; Myoclonus; Morphine; Opioid Rotation.
Introduction and Patient Profile: Pain is a common complaint, and pain control is frequently challenging. End-stage renal disease (ESRD) patients constitute a special population in whom commonly-prescribed medications, including pain medications, must be adjusted or discontinued for safety. We describe a patient with ESRD in whom myoclonus developed after he received 60 days of morphine. Interventions and Outcomes: Morphine was discontinued, and symptoms resolved. Discussion: Morphine is hepatically metabolized to morphine-3-glucuronide (M3G), which is renally cleared. In patients with ESRD, M3G and other metabolites are neither renally cleared nor easily removed by dialysis, increasing the risk of neuroexcitatory symptoms such as myoclonus. The use and dosing of renally-cleared medications in ESRD patients should be carefully reviewed by prescribers and pharmacists.

Published: January 1, 2014
Senior Editor: Jack Mettler
Junior Editor: Margaret Chi
DOI: Pending
Stahl VL, Ahmad HI, Novak JE. Morphine-Induced Myoclonus in a Patient with End-Stage Renal Disease. Medical Student Research Journal. 2014;3(Winter):023-5.
1. Munar M, Singh H. Drug Dosing Adjustments in Patients with Chronic Kidney Disease. American Family Physician. May 2007;75(10):1487-1496.
2. Pauli-Magnus C, Hofmann U, Mikus G, Kuhlmann U, Mettang T. Pharmocokinetics of Morphine and its Glucuronides Following Intravenous Administration of Morphine in Patients Undergoing Continuous Ambulatory Peritoneal Dialysis. Nephrology Dialysis Transplantation. April 1999;14(4):903-909.
3. Dean M. Opioids in Renal Failure and Dialysis Patients. Journal of Pain and Symptom Management. November 2004;28(5):497-504.
4. Andersen G, Christrup L, Sjøgren P. Relationships Among Morphine Metabolism, Pain and Side Effects During Long-Term Treatment: An Update. Journal of Pain and Symptom Management. January 2003;25(1):74-91.
5. Hemstapat K, Monteith G, Smith D, Smith MT. Morphine-3-Glucuronide’s Neuro-Excitatory Effects Are Mediated via Indirect Activation of N-Methyl-D-Aspartic Acid Receptors: Mechanistic Studies in Embryonic Cultured Hippocampal Neurones. Anesthesia and Analgesia. August 2003;97(2):494-505.
6. Indelicato RA, Portenoy RK. Opioid Rotation in the Management of Refractory Cancer Pain. Journal of Clinical Oncology. January 2002;20(1):348-352.
7. Narabayashi M, Saijo Y, Takenoshita S, Chida M, Shimoyama N, Miura T, Tani K, Nishimura K, Onozawa Y, Hosokawa T, Kamoto T, Tsushima T. Opioid Rotation from Oral Morphine to Oral Oxycodone in Cancer Patients with Intolerable Adverse Effects: An Open-Label Trial. Japanese Journal of Clinical Oncology. April 2008;38(4):296-304.
8. Gagnon DJ, Jwo K. Tremors and Agitation Following Low-Dose Intravenous Hydromorphone Administration in a Patient with Kidney Dysfunction. Annals of Pharmacotherapy. July/August 2013;47(7-8);e34.
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Winter 2014 – Declaration of Helsinki: What Does the Future Hold?

Declaration of Helsinki: What Does the Future Hold?
Margaret D. Chi* and Michelle A. Dwyer
Author Affiliations:
College of Human Medicine, Michigan State University, East Lansing, MI, USA

Corresponding author: Margaret D. Chi MPH; chimarga[at]

Key Words: Research Ethics; Medicine; Human Research Subject Protection; Informed Consent; Helsinki Declaration; Bioethics
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Corresponding author: Margaret D. Chi MPH; chimarga[at]

Key Words: Research Ethics; Medicine; Human Research Subject Protection; Informed Consent; Helsinki Declaration; Bioethics
Within the world of medical research, the Declaration of Helsinki (DoH) has long been considered the cornerstone document explaining the “rules” of ethical human research. Developed in 1964 by the World Medical Association to protect the rights of research subjects, it originally contained a set of 11 articles explaining the basic ethical duties of physicians in regards to research. The original version took aspects of the Nuremburg Code and Declaration of Geneva to incorporate human experimentation with the physician’s ethical role in the process and delineated a patient’s rights of informed consent, privacy and safety1,3. Since then, it has undergone seven revisions and grown in length from 11 to now 37 articles, with categories ranging from General Principles to Risks to Informed Consent ( Though considered comprehensive and accurate in some aspects, it has not been without controversy over the years. Therefore, this year, which commemorates the 50th anniversary of the document, we must ask, how has the relevance of DoH changed, and will it change further in the future?

Published: January 1, 2014
Senior Editor: N/A
Junior Editor: N/A
DOI: Pending
Chi MD, Dwyer MA. Declaration of Helsinki: What Does the Future Hold?. Medical Student Research Journal. 2014;3(Winter):20-2.
1. Carlson, RV, Boyd KM, Webb, DJ. The Revision of the Declaration of Helsinki: Past, present and future. British Journal of Clinical Pharmacology. 2004; 57(6):695-713.
2. Nbebele, P. The Declaration of Helsinki, 50 years later. JAMA. 2013; 310(20):2145-6.

3. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles form medical research involving human subjects. JAMA. 2013; 310(20):2191-4.
4. Millium, J, Wendler, D, Emmanuel E. The 50th Anniversary of the Declaration of Helsinki: progress but many remaining challenges. JAMA. 2013; 310(20):2143-4.
5. Coyne, J. Revised Ethical Principles Have Profound Implications for Psychological Research. PLOS Blogs. 2013. [cited 30 November, 2013].


Winter 2014 – Spirit Queen

Spirit Queen.
Masaki Nagamine
Author Affiliations:
College of Human Medicine, Michigan State University, Grand Rapids, MI, USA


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Corresponding Author: Masaki Nagamine; masakinagamine[at]
Key Words: N/A
Preface: In my childhood, I lived with a family member suffering from paranoid schizophrenia. The painting is my interpretation of the inner turmoil that this family member faces regularly. It is my hope that the viewers of this painting can gain some insight into the difficulties involved in living with a chronic mental illness that cannot be fully understood. The painting depicts a person with paranoid schizophrenia attempting to balance her perceived reality between cultural beliefs, logical reasoning, and schizophrenic delusion. The image shows a young child looking down on her brain encased in a coiled golden ribbon to illustrate the dichotomy of the body and mind. The four corners of the painting are weathered and deteriorating to demonstrate the progressive nature
of the disease/illness.
Published: January 1, 2014
Senior Editor: N/A
Junior Editor: N/A
DOI: Pending
Nagamine M. Spirit Queen. Medical Student Research Journal. 2014;3(Winter):18-9.

Winter 2014 – Letter From the Editors

Letter From the Editors.
Kevin C. Patterson and Jessica L. Wummel
Author Affiliations:
College of Human Medicine, Michigan State University, East Lansing, MI, USA

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Corresponding Author: Kevin C. Patterson; patte297[at]
Key Words: N/A
The editors of MSRJ would like to extend our warm wishes in the winter season and hope that it has
been filled with joy, family, and good fortune. We are very excited to introduce the first issue of 2014, as well as the second issue of the 20132014 academic year. As medical students around the world return to their
books and clinic duties, we present educational and stimulating new articles. The published works in this
issue highlight the efforts of students from Creighton University School of Medicine, Wayne State University
School of Medicine, and Michigan State University College of Human Medicine.
Published: January 1, 2014
Senior Editor: N/A
Junior Editor: N/A
DOI: Pending
Patterson KC, Wummel JL. Letter From the Editors. Medical Student Research Journal. 2014;3(Winter):17.