- Email: [email protected]
6 Communication in Genetics and Genomics
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Abstracts and Learning Outcomes / European Journal of Oncology Nursing 16S1 (2012) S1–S20
3 Changing the Concept of Cervical Cancer Screening in Europe – the Example of HPV DNA Introduction S. de Sanjose1 . 1 Institut Catal` a d’Oncologia, Unit of Infections and Cancer, Barcelona, Spain Cervical cancer represents major disease burden worldwide. Every year more than half a million new cases worldwide are being diagnosed together with an additional burden that includes preneoplasic lesions that can account for about 5% of the screened women. Screening for cervical cancer through cervical cytology has decreased burden of disease in those countries that have implemented population-based interventions. Recently, highly validated assays detecting HPV DNA have shown to considerably improve the screening impact. Further, the recently available HPV vaccines provide a new hope towards cervical cancer elimination. Vaccines prevent the infection of HPV 16 & HPV 18, the two most common and aggresive types leading to invasive cancer of the cervix. These vaccines have been incorporated in several immunization programmes in several countries. Existent vaccines have the potential to reduce around 70% of invasive cervical cancer and a similar proportion of pre-neoplasic lesions. This can only be achieved through high coverage of the susceptible population. An organized introduction of the vaccine to girls and young women together with a screening strategy post-vaccination have shown to be very cost-effective approach with a major population impact.
Parallel Session: Advances in Genomics and Personalised Medicine: Implications for Cancer Care 4 Genomics and Personalised Medicine G. Pichert1 . 1 Klinik Engeried, Onocare, Berne, Switzerland Within the last four decades enormous advances have been made in our knowledge of genes, their functions and interactions with each other and the environment. This knowledge will fundamentally alter medicine as it is practiced today, change patient care as well as health services and ultimately translate into personalised medicine with more accurate disease risk assessment, individualized prevention and treatment. However, many obstacles have to be overcome on the way to achieve this goal. In oncology, these are identifying key genetic aberrations that drive cancer growth, identifying biomarkers that predict cancer, searching for diagnostic tests and treatments tailored to the changing genomic profile of individual cancers and assessing the clinical utility of new tools for response and relapse prediction such as tumor gene expression profiles in randomized clinical trials. Further challenges are to develop large biobanks to detect the small impact of common genetic variations on disease development and to create sufficient IT capacities to analyze the huge amount of genomic data and link it with lifestyle and environmental data, to develop new tools for diagnosis and treatment and to further genomic research. Finally, these new diagnostic tests and treatments will be expensive, and publicly funded health care systems need to figure out a way to afford them amid ever increasing financial pressure. Reference(s) Foundation for Genomics and Population Health: Genetic and mainstream medicine. Service development and integration. March 2011. www.phgfoundation.org (last accessed 28.12.2011). House of Lords, Science and Technology Committee, 2nd Report of Session 2008–09: Genomic Medicine, Volume I: Report, Ordered to be printed 2 June 2009 and published 7 July 2009. www.publications .parliament.uk/pa/ld200809/ldselect/ldsctech/107/10702.htm (last accessed 28.12.2011).
Stratton MR. Exploring the Genomes of Cancer Cells: Progress and Promise. Science 331; pp 1553–1558, 2011. Bloss CS et al. Genomics for disease treatment and prevention. Psychiatr Clin North Am 34: 147–166, 2011. Gasparini G and Longo R. The paradigm of personalized therapy in oncology. Expert Opin Ther Targets. 2011 Nov 11 [Epub ahead of print].
5 How Genomics Will Change our Practice P. Rieger Trahan1 . 1 Oncology Nursing Society (ONS), Pittsburgh, USA As scientific discoveries continue within genetics and genomics, the prediction of a more personalised approach to the management of cancer is rapidly becoming a clinical reality. Increasingly, new treatment modalities are based not only on the tissue type of a particular cancer, but upon the genetic changes within that cancer. Scientists seek to understand the oncogenic driving change within a cell and then base treatment on that driver. We stand on the cusp of beginning to fulfill the promise of offering the right dose for the right indication for the right patient at the right time. In the past five years, we have seen the use of tests that analyze genetic changes in breast cancer as a means to determine best therapy or whether women need conservative versus aggressive therapy. The use of targeted therapy has expanded significantly with the approval of new targeted agents for melanoma, lung cancer, hematologic malignancies, and breast cancer. We are seeing cancer treatment evolve from a battle to kill all cells to one of a more chronic disease focus where disease is controlled and patients may be on therapy for much longer periods of time. Nurses must know the basic principles of genetics and the biology of cancer so they may understand the principles behind new strategies to diagnose, detect, and characterize tumors. They are key to educating patients and families about these new therapies, to assuring adherence to oral therapies, and to managing a radically different profile of side effects associated with new therapies. Reference(s) Bartlett, D. (2011). Drug therapy gets personal with genetic profiling. American Nurse Today, 6, 23–28. Bedell, C.H. (2003). A changing paradigm for cancer treatment: The advent of new oral chemotherapy agents. Clinical Journal of Oncology Nursing, 7(6, Suppl.), 5–9. Calzone, K.A., Masny, A., & Jenkins, J. (Eds.). (2010). Genetics and genomics in oncology nursing practice (2nd ed.). Pittsburgh, PA: Oncology Nursing Society. Gonzalez-Angulo, A.M., Hennessy, B.T.J., & Mills, G.B. (2010). Future of personalized medicine in oncology: A systems biology approach. Journal of Clinical Oncology, 28, 2777–2783. MacConaill, L.E., & Garraway, L.A. (2010). Biology of neoplasia: Clinical implications of the cancer genome. Journal of Clinical Oncology, 28, 5219– 5228. Petrelli, N.J., et al. (2009). Clinical cancer advances 2009: Major research advances in cancer treatment, prevention, and screening—A report from the American Society of Clinical Oncology. Journal of Clinical Oncology, 27, 6052–6069.
6 Communication in Genetics and Genomics A. Murphy1 . 1 Hˆ opitaux Universitaires de Gen`eve, Service d’Oncologie, Geneva, Switzerland We all know that communication is a vast topic and that communication skills are essentials in all aspects of health care and of course of nursing in oncology. During this session we will explore what is so specific about the nurses’ role in communication in genetics and genomics. The first key point is that, from the sequencing of the human genome in 2003, it is clear that both genetics and genomics are becoming relevant in all medical fields and more specifically for cancer care; the knowledge of the molecular basis of cancer is
Abstracts and Learning Outcomes / European Journal of Oncology Nursing 16S1 (2012) S1–S20
essential in prevention, screening, diagnosis, prognosis and now also in treatment choice. The second key point is that nurses have a great challenge to develop specific competencies in a field characterized by ongoing research leading to new discoveries and their possible implication for clinical practice. Third key point is that while genomics refers to the study of all the genes of one person and has an impact on this person’s care; genetics refers to the study of genes and can possibly implicate the family of an individual and lead to the need of communication of accurate information inside the family and its possible difficulties. Last point is that genetics and genomics knowledge has opened the way to the emerging field of predictive medicine with the possibility of making an early diagnosis or even preventing cancer by adequate surveillance and preventive measures. Reference(s) J. Jeankins, K. A. Calzone (2007). Establishing the essential nursing competencies for genetics and genomics. Journal of Nursing Scholarship; 37: 1, 10–16 D. H. Lea, H. Skirton, C. Read & J. K. Williams (2011). Implications for Educating the next generation of nurses on genetics and genomics in the 21st century. Journal of Nursing Scholarship; 43: 1, 3–12 National Human Genome Research Institute – http://genome.gov/ www.orphanet.org Genetics and your practice – www.marchofdimes.com/gyponline/index.bm2
Parallel Session: Management of Skin Cancer and Skin Problems 7 New Developments in the Systemic Treatment of Melanoma A.S.V. Adriaansz1 . 1 The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Medical Oncology/Daycare, Amsterdam, The Netherlands Introduction: Melanoma is the most agressive form of skincancer and global incidence is rapidly increasing. Most of the new cases of melanoma will be cured by surgery. However for patients with advanced melanoma there is a high unmed need for new systemic therapies. In the last few years there have been two new developments: ipilimumab, a fully human monoclonal antibody that mediates an antitumor immune response by blocking the cytotoxic T-lymfocyte antigen-4 (CTLA-4) and vemurafenib, a small molecule that inhibits the protein BRAF which is mutated in almost 60% of the patients with melanoma. Both treatments have their own specific side effects. These side effects can be serious as heavy sunburn and the expression of squamous cell carcinoma (vemurafenib) or may even be life threatening by generating serious inflammation (ipilimumab). Methods: During this session the profile of side effects caused by these two treatments will be considered and the significance and consequences for nursing practice, patient education, management of side effects and nursing intervention will be addressed. Results: At the end of the session the nurse will be able to name: – and recognize the side effects of both treatments – the risk factors of the side effects and how to grade them (CTC version 4.0) – the nursing (and medical) interventions for managing side effects – the importance of patient education Conclusion: Managing the side effects of both treatments ipilimumab and vemurafenib have consequences for nursing practice. Specialized nursing skills are very important for effective nursing and medical interventions and require specific knowledge.
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Reference(s) [1] Hodi FS, O’day SJ, McDermott DF, et al. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N Engl J Med 2010 Aug 19; 363(8): 711–23. [2] Tarhini AA, Kirkwood JM. CTLA-4-Blocking Immunotherapy with Ipilimumab for Advanced Melanoma. Oncology 2010 Dec; 24(14): 1302, 1304. [3] Thumar JR, Kluger HM. Ipilimumab: A Promising Immunotherapy for Melanoma. Oncology 2010 Dec; 24(14): 1280–8. [4] Chapman PB, Hauschild A, Haanen JB, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutations. N Engl J Med. 2011 Jun 30; 364(26): 2507–16. [5] Nikolaou VA, Stratogos AJ, Flaherty KT, et al. Melanoma: New Insight and New Therapie. J Invest Dermatol. 2012 Jan 5. doi:10.1038/ jid.2011.421
8 Impact and Management of Malignant Wounds B. Lund-Nielsen1 . 1 The Finsen Center University Hospital, Department of Oncology Finsen Centre, Copenhagen, Denmark Introduction: 5–10% of all cancer patients develop malignant wounds [1]. These wounds form from underlying tumors that penetrate the skin and result in exudation and in malodors wounds that affect patients’ psychosocial conditions [2]. The management of malignant wounds comprises anti-neoplasm treatment, optimal wound treatment, psychosocial and existential care. Materials: A randomized intervention study (n = 75) compared the effects of two wound treatments [3]: Honey-coated versus silver-coated bandages – both treatments are supplemented with conversations structured after the cognitive model – and relaxation training [4,5]. Methods: Photography using Quantify-Image-Central software, wound swabbing, wound morphology registration, VAS scoring (pain, exudation, malodor), psychometric testing (EORTC-QLQ-C30, HADS, mini-MAC) and interviewing Results: There was no statistically significant difference in wound size, cleanliness of wound, exudation, malodor, pain and bacteriology between the groups. Pooled data analysis from the two groups showed an improvement from baseline to post-intervention with respect to diminished wound size in 62% of patients and increased cleanliness 58% of patients (n = 69). There was statistically significant improvement in the patients’ estimation of malodor (p = 0.007), exudation (p < 0.0001), anxiety (p = 0.007) and depression (p = 0.049) Conclusion: Malignant wounds are chronic wounds that lead to malodor, exudation and psychosocial problems. Reduced wound size in 62% of the population and increased cleanliness in 58% from baseline to post-intervention were indicative of improved healing. A statistically significant reduction in malodor, anxiety and depression with both treatments improved the patients’ wellbeing and overall situation The results indicate that an intervention using silver-coated or honey-coated bandages, supplemented with cognitive dialogue and relaxation training should be considered as a future treatment option for patients with malignant wounds and advanced stage cancer. Reference(s) [1] Alexander S. Malignant fungating wounds: epidemiology, aetiology, presentation and assessment. J Wound Care 2009; 18(7): 273–80. [2] Selby T. Managing exudate in malignant fungating wounds and solving problems for patients. Nurs Times 2009 May 12; 105(18): 14–7. [3] Lund-Nielsen B; Adamsen L; Kolmos HJ; Rørth M; Tolver A, Gottrup F. The effect of honey-coated bandages compared with silver-coated bandages on treatment of malignant wounds—a randomized study. Wound Repair and Regeneration 2011 [Epub 2011 Oct 13]. PMID: 22092836.
Abstracts and Learning Outcomes / European Journal of Oncology Nursing 16S1 (2012) S1–S20
3 Changing the Concept of Cervical Cancer Screening in Europe – the Example of HPV DNA Introduction S. de Sanjose1 . 1 Institut Catal` a d’Oncologia, Unit of Infections and Cancer, Barcelona, Spain Cervical cancer represents major disease burden worldwide. Every year more than half a million new cases worldwide are being diagnosed together with an additional burden that includes preneoplasic lesions that can account for about 5% of the screened women. Screening for cervical cancer through cervical cytology has decreased burden of disease in those countries that have implemented population-based interventions. Recently, highly validated assays detecting HPV DNA have shown to considerably improve the screening impact. Further, the recently available HPV vaccines provide a new hope towards cervical cancer elimination. Vaccines prevent the infection of HPV 16 & HPV 18, the two most common and aggresive types leading to invasive cancer of the cervix. These vaccines have been incorporated in several immunization programmes in several countries. Existent vaccines have the potential to reduce around 70% of invasive cervical cancer and a similar proportion of pre-neoplasic lesions. This can only be achieved through high coverage of the susceptible population. An organized introduction of the vaccine to girls and young women together with a screening strategy post-vaccination have shown to be very cost-effective approach with a major population impact.
Parallel Session: Advances in Genomics and Personalised Medicine: Implications for Cancer Care 4 Genomics and Personalised Medicine G. Pichert1 . 1 Klinik Engeried, Onocare, Berne, Switzerland Within the last four decades enormous advances have been made in our knowledge of genes, their functions and interactions with each other and the environment. This knowledge will fundamentally alter medicine as it is practiced today, change patient care as well as health services and ultimately translate into personalised medicine with more accurate disease risk assessment, individualized prevention and treatment. However, many obstacles have to be overcome on the way to achieve this goal. In oncology, these are identifying key genetic aberrations that drive cancer growth, identifying biomarkers that predict cancer, searching for diagnostic tests and treatments tailored to the changing genomic profile of individual cancers and assessing the clinical utility of new tools for response and relapse prediction such as tumor gene expression profiles in randomized clinical trials. Further challenges are to develop large biobanks to detect the small impact of common genetic variations on disease development and to create sufficient IT capacities to analyze the huge amount of genomic data and link it with lifestyle and environmental data, to develop new tools for diagnosis and treatment and to further genomic research. Finally, these new diagnostic tests and treatments will be expensive, and publicly funded health care systems need to figure out a way to afford them amid ever increasing financial pressure. Reference(s) Foundation for Genomics and Population Health: Genetic and mainstream medicine. Service development and integration. March 2011. www.phgfoundation.org (last accessed 28.12.2011). House of Lords, Science and Technology Committee, 2nd Report of Session 2008–09: Genomic Medicine, Volume I: Report, Ordered to be printed 2 June 2009 and published 7 July 2009. www.publications .parliament.uk/pa/ld200809/ldselect/ldsctech/107/10702.htm (last accessed 28.12.2011).
Stratton MR. Exploring the Genomes of Cancer Cells: Progress and Promise. Science 331; pp 1553–1558, 2011. Bloss CS et al. Genomics for disease treatment and prevention. Psychiatr Clin North Am 34: 147–166, 2011. Gasparini G and Longo R. The paradigm of personalized therapy in oncology. Expert Opin Ther Targets. 2011 Nov 11 [Epub ahead of print].
5 How Genomics Will Change our Practice P. Rieger Trahan1 . 1 Oncology Nursing Society (ONS), Pittsburgh, USA As scientific discoveries continue within genetics and genomics, the prediction of a more personalised approach to the management of cancer is rapidly becoming a clinical reality. Increasingly, new treatment modalities are based not only on the tissue type of a particular cancer, but upon the genetic changes within that cancer. Scientists seek to understand the oncogenic driving change within a cell and then base treatment on that driver. We stand on the cusp of beginning to fulfill the promise of offering the right dose for the right indication for the right patient at the right time. In the past five years, we have seen the use of tests that analyze genetic changes in breast cancer as a means to determine best therapy or whether women need conservative versus aggressive therapy. The use of targeted therapy has expanded significantly with the approval of new targeted agents for melanoma, lung cancer, hematologic malignancies, and breast cancer. We are seeing cancer treatment evolve from a battle to kill all cells to one of a more chronic disease focus where disease is controlled and patients may be on therapy for much longer periods of time. Nurses must know the basic principles of genetics and the biology of cancer so they may understand the principles behind new strategies to diagnose, detect, and characterize tumors. They are key to educating patients and families about these new therapies, to assuring adherence to oral therapies, and to managing a radically different profile of side effects associated with new therapies. Reference(s) Bartlett, D. (2011). Drug therapy gets personal with genetic profiling. American Nurse Today, 6, 23–28. Bedell, C.H. (2003). A changing paradigm for cancer treatment: The advent of new oral chemotherapy agents. Clinical Journal of Oncology Nursing, 7(6, Suppl.), 5–9. Calzone, K.A., Masny, A., & Jenkins, J. (Eds.). (2010). Genetics and genomics in oncology nursing practice (2nd ed.). Pittsburgh, PA: Oncology Nursing Society. Gonzalez-Angulo, A.M., Hennessy, B.T.J., & Mills, G.B. (2010). Future of personalized medicine in oncology: A systems biology approach. Journal of Clinical Oncology, 28, 2777–2783. MacConaill, L.E., & Garraway, L.A. (2010). Biology of neoplasia: Clinical implications of the cancer genome. Journal of Clinical Oncology, 28, 5219– 5228. Petrelli, N.J., et al. (2009). Clinical cancer advances 2009: Major research advances in cancer treatment, prevention, and screening—A report from the American Society of Clinical Oncology. Journal of Clinical Oncology, 27, 6052–6069.
6 Communication in Genetics and Genomics A. Murphy1 . 1 Hˆ opitaux Universitaires de Gen`eve, Service d’Oncologie, Geneva, Switzerland We all know that communication is a vast topic and that communication skills are essentials in all aspects of health care and of course of nursing in oncology. During this session we will explore what is so specific about the nurses’ role in communication in genetics and genomics. The first key point is that, from the sequencing of the human genome in 2003, it is clear that both genetics and genomics are becoming relevant in all medical fields and more specifically for cancer care; the knowledge of the molecular basis of cancer is
Abstracts and Learning Outcomes / European Journal of Oncology Nursing 16S1 (2012) S1–S20
essential in prevention, screening, diagnosis, prognosis and now also in treatment choice. The second key point is that nurses have a great challenge to develop specific competencies in a field characterized by ongoing research leading to new discoveries and their possible implication for clinical practice. Third key point is that while genomics refers to the study of all the genes of one person and has an impact on this person’s care; genetics refers to the study of genes and can possibly implicate the family of an individual and lead to the need of communication of accurate information inside the family and its possible difficulties. Last point is that genetics and genomics knowledge has opened the way to the emerging field of predictive medicine with the possibility of making an early diagnosis or even preventing cancer by adequate surveillance and preventive measures. Reference(s) J. Jeankins, K. A. Calzone (2007). Establishing the essential nursing competencies for genetics and genomics. Journal of Nursing Scholarship; 37: 1, 10–16 D. H. Lea, H. Skirton, C. Read & J. K. Williams (2011). Implications for Educating the next generation of nurses on genetics and genomics in the 21st century. Journal of Nursing Scholarship; 43: 1, 3–12 National Human Genome Research Institute – http://genome.gov/ www.orphanet.org Genetics and your practice – www.marchofdimes.com/gyponline/index.bm2
Parallel Session: Management of Skin Cancer and Skin Problems 7 New Developments in the Systemic Treatment of Melanoma A.S.V. Adriaansz1 . 1 The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Medical Oncology/Daycare, Amsterdam, The Netherlands Introduction: Melanoma is the most agressive form of skincancer and global incidence is rapidly increasing. Most of the new cases of melanoma will be cured by surgery. However for patients with advanced melanoma there is a high unmed need for new systemic therapies. In the last few years there have been two new developments: ipilimumab, a fully human monoclonal antibody that mediates an antitumor immune response by blocking the cytotoxic T-lymfocyte antigen-4 (CTLA-4) and vemurafenib, a small molecule that inhibits the protein BRAF which is mutated in almost 60% of the patients with melanoma. Both treatments have their own specific side effects. These side effects can be serious as heavy sunburn and the expression of squamous cell carcinoma (vemurafenib) or may even be life threatening by generating serious inflammation (ipilimumab). Methods: During this session the profile of side effects caused by these two treatments will be considered and the significance and consequences for nursing practice, patient education, management of side effects and nursing intervention will be addressed. Results: At the end of the session the nurse will be able to name: – and recognize the side effects of both treatments – the risk factors of the side effects and how to grade them (CTC version 4.0) – the nursing (and medical) interventions for managing side effects – the importance of patient education Conclusion: Managing the side effects of both treatments ipilimumab and vemurafenib have consequences for nursing practice. Specialized nursing skills are very important for effective nursing and medical interventions and require specific knowledge.
S3
Reference(s) [1] Hodi FS, O’day SJ, McDermott DF, et al. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N Engl J Med 2010 Aug 19; 363(8): 711–23. [2] Tarhini AA, Kirkwood JM. CTLA-4-Blocking Immunotherapy with Ipilimumab for Advanced Melanoma. Oncology 2010 Dec; 24(14): 1302, 1304. [3] Thumar JR, Kluger HM. Ipilimumab: A Promising Immunotherapy for Melanoma. Oncology 2010 Dec; 24(14): 1280–8. [4] Chapman PB, Hauschild A, Haanen JB, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutations. N Engl J Med. 2011 Jun 30; 364(26): 2507–16. [5] Nikolaou VA, Stratogos AJ, Flaherty KT, et al. Melanoma: New Insight and New Therapie. J Invest Dermatol. 2012 Jan 5. doi:10.1038/ jid.2011.421
8 Impact and Management of Malignant Wounds B. Lund-Nielsen1 . 1 The Finsen Center University Hospital, Department of Oncology Finsen Centre, Copenhagen, Denmark Introduction: 5–10% of all cancer patients develop malignant wounds [1]. These wounds form from underlying tumors that penetrate the skin and result in exudation and in malodors wounds that affect patients’ psychosocial conditions [2]. The management of malignant wounds comprises anti-neoplasm treatment, optimal wound treatment, psychosocial and existential care. Materials: A randomized intervention study (n = 75) compared the effects of two wound treatments [3]: Honey-coated versus silver-coated bandages – both treatments are supplemented with conversations structured after the cognitive model – and relaxation training [4,5]. Methods: Photography using Quantify-Image-Central software, wound swabbing, wound morphology registration, VAS scoring (pain, exudation, malodor), psychometric testing (EORTC-QLQ-C30, HADS, mini-MAC) and interviewing Results: There was no statistically significant difference in wound size, cleanliness of wound, exudation, malodor, pain and bacteriology between the groups. Pooled data analysis from the two groups showed an improvement from baseline to post-intervention with respect to diminished wound size in 62% of patients and increased cleanliness 58% of patients (n = 69). There was statistically significant improvement in the patients’ estimation of malodor (p = 0.007), exudation (p < 0.0001), anxiety (p = 0.007) and depression (p = 0.049) Conclusion: Malignant wounds are chronic wounds that lead to malodor, exudation and psychosocial problems. Reduced wound size in 62% of the population and increased cleanliness in 58% from baseline to post-intervention were indicative of improved healing. A statistically significant reduction in malodor, anxiety and depression with both treatments improved the patients’ wellbeing and overall situation The results indicate that an intervention using silver-coated or honey-coated bandages, supplemented with cognitive dialogue and relaxation training should be considered as a future treatment option for patients with malignant wounds and advanced stage cancer. Reference(s) [1] Alexander S. Malignant fungating wounds: epidemiology, aetiology, presentation and assessment. J Wound Care 2009; 18(7): 273–80. [2] Selby T. Managing exudate in malignant fungating wounds and solving problems for patients. Nurs Times 2009 May 12; 105(18): 14–7. [3] Lund-Nielsen B; Adamsen L; Kolmos HJ; Rørth M; Tolver A, Gottrup F. The effect of honey-coated bandages compared with silver-coated bandages on treatment of malignant wounds—a randomized study. Wound Repair and Regeneration 2011 [Epub 2011 Oct 13]. PMID: 22092836.