Quality of life of esophagectomized patients: adenocarcinoma versus squamous cell carcinoma

Abstracts

OBJECTIVE: To evaluate and compare the quality of life (QOL) of patients undergoing esophagectomy for treatment of adenocarcinoma of the esophagogastric junction and squamous cell carcinoma. METHODS: We conducted a cross-sectional study in postoperative patients submitted to esophagectomy for adenocarcinoma of the esophagogastric junction (ACA) and squamous cell carcinoma (SCC), using the SF-36 questionnaire applied in 24 patients (10 ACAs and 14 SCCs), from the 5th months postoperatively, including clinical symptoms and weight change. RESULTS: The assessment of QOL showed the best functional capacity (p = 0.018) in the ACA group. There was a correlation between the fields "mental health" and "Role of Emotions" (p = 0.003) and between "pain" and "physical aspects limitation" (p = 0.003) in both histological types. Weight loss was greater in ACA (45.9 kg), with no significant difference between current BMI (p> 0.66). Dysphagia was reported by 83.3% of patients, anorexia by58.3%, chewing difficulty by 42%, nausea and vomiting by 41.7% and diarrhea by 29.2%, with no correlation with QOL reported (p> 0.05). CONCLUSION: The highest score for functional capacity indicates that ACA patients were able to perform all types of physical activity, including the more demanding, at a higher level than patients with SCC. Some symptoms persisted postoperatively, but did not affect the quality of life of patients.

Adenocarcinoma; Squamous Cell Carcinoma; Quality of life; Esophagectomy; Swallowing disorders

OBJETIVO: Avaliar e comparar a qualidade de vida de pacientes esofagectomizados para tratamento de adenocarcinoma da junção esofagogástrica e de carcinoma epidermoide. MÉTODOS: estudo transversal no pós-operatório de doentes esofagectomizados por adenocarcinoma da junção esofagogástrica (Adenoca) e carcinoma epidermóide (CEC), empregando o questionário SF-36 aplicado em 24 pacientes (10 por Adenoca e 14 por CEC), a partir do 5º mês de pós-operatório, incluindo os sintomas clínicos e a variação de peso. RESULTADOS: A avaliação da QV mostrou melhor resultado de capacidade funcional (p=0,018) para o grupo Adenoca. Houve correlação entre os domínios "saúde mental" e "limitação por aspectos emocionais" (p=0,003) e entre "dor" e "limitação por aspectos físicos" (p=0,003) nos dois tipos histológicos. A perda de peso foi maior nos esofagectomizados por Adenoca (45,9Kg), sem diferença significativa entre o IMC atual (p>0,66). A disfagia foi relatada por 83,3% dos pacientes, a anorexia por 58,3%, a dificuldade de mastigação por 42%, a náuseas e os vômitos por 41,7% e a diarréia por 29,2%, sem correlação com a QV relatada (p>0,05). CONCLUSÃO: O escore mais alto para capacidade funcional indica que o paciente com Adenoca foi capaz de realizar todo tipo de atividade física, incluindo as mais vigorosas em um nível maior que o paciente com CEC. Alguns sintomas persistiram no pós-operatório, porém não interferiram na qualidade de vida dos pacientes.

Adenocarcinoma; Carcinoma de células escamosas; Qualidade de vida; Esofagectomia; Transtornos de deglutição

ORIGINAL ARTICLE

Quality of life of esophagectomized patients: adenocarcinoma versus squamous cell carcinoma

Maricilda Regina Pereira^I; Luiz Roberto Lopes, TCBC-SP^II; Nelson Adami Andreollo TCBC-SP^III

^INutritionist, Graduate, Post-Graduation in Surgical Sciences, Faculty of Medical Sciences, UNICAMP

^IIFull Professor, Discipline of Digestive System Diseases and Gastrocenter, Department of Surgery, Faculty of Medical Sciences, UNICAMP

^IIIProfessor, Discipline of Digestive System Diseases and Gastrocenter, Department of Surgery, Faculty of Medical Sciences, UNICAMP

Correspondence to

ABSTRACT

OBJECTIVE: To evaluate and compare the quality of life (QOL) of patients undergoing esophagectomy for treatment of adenocarcinoma of the esophagogastric junction and squamous cell carcinoma.

METHODS: We conducted a cross-sectional study in postoperative patients submitted to esophagectomy for adenocarcinoma of the esophagogastric junction (ACA) and squamous cell carcinoma (SCC), using the SF-36 questionnaire applied in 24 patients (10 ACAs and 14 SCCs), from the 5th months postoperatively, including clinical symptoms and weight change.

RESULTS: The assessment of QOL showed the best functional capacity (p = 0.018) in the ACA group. There was a correlation between the domains "mental health" and "Role of Emotions" (p = 0.003) and between "pain" and "physical aspects limitation" (p = 0.003) in both histological types. Weight loss was greater in ACA (45.9 kg), with no significant difference between current BMI (p> 0.66). Dysphagia was reported by 83.3% of patients, anorexia by58.3%, chewing difficulty by 42%, nausea and vomiting by 41.7% and diarrhea by 29.2%, with no correlation with QOL reported (p> 0.05).

CONCLUSION: The highest score for functional capacity indicates that ACA patients were able to perform all types of physical activity, including the more demanding, at a higher level than patients with SCC. Some symptoms persisted postoperatively, but did not affect the quality of life of patients.

Key words: Adenocarcinoma. Carcinoma, squamous cell. Quality of life. Esophagectomy. Deglutition disorders.

INTRODUCTION

Squamous cell carcinoma cell carcinoma (SCC) used to be the main focus of attention of the studies on esophageal cancer¹. However, increased incidence of adenocarcinoma of the esophagogastric junction (Adenoca) has been reported in the last four decades².

The SCC is strongly correlated with smoking and alcohol consumption, and the adenocarcinoma of the esophagogastric junction is associated with Barrett's esophagus and gastroesophageal reflux³. Evidence suggests that obesity is positively associated with risk of developing esophageal Adenoca, while malnutrition has been linked to SCC⁴.

There are comparative analysis of the quality of life of patients submitted to esophagectomy according to some surgical aspects, such as comparing the limited trans-hiatal resection to extensive transthoracic resection⁵; between reconstruction with gastric tube and interposing the colon⁶; comparison between curative esophagectomy and palliation^7,8; or even the comparison between the domains of quality of life with symptoms (physical and emotional) and factors related to illness and operation⁹. We did not found in the literature the possible differences between the quality of life of patients submitted to esophagectomy for Adenoca of the esophagogastric junction and the one of those submitted to esophagectomy by SCC.

De Boer et al. compared the quality of life of patients undergoing esophagectomy for Adenoca three years after trans-hiatal or transthoracic resection⁵. Moreover, Rosmolen et al., in a longitudinal study, analyzed the quality of life among survivors of long periods⁸ (minimum two years) after resection and reconstruction with transmediastinal gastric tube in 100 patients, also in patients with Adenoca. De Boer et al., in another longitudinal study, included 67% of Adenoca in the total sample studied and 28% of SCC⁹.

In the first six months after surgery, during a variable period of time the patient experiences undesirable symptoms, such as low food intake, nausea, ongoing weight loss, feeling of weakness, diarrhea, dysphagia and pain¹⁰, and a quality of life that can be greatly impaired, returning to preoperative levels^7,11. Thus, once it is possible to better evaluate and investigate these symptoms, they can certainly be minimized through guidelines and treatments, improving the quality of life of the patient.

The objective of this study was to evaluate and compare the quality of life of patients submitted to esophagectomy for adenocarcinoma of the esophagogastric junction and squamous cell carcinoma, from the fifth month postoperatively, using the generic SF-36, and to investigate weight variations, the presence of dysphagia, anorexia, nausea, vomiting, diarrhea and constipation and relate them to quality of life.

METHODS

We performed transversal analyses of 24 patients undergoing esophagectomy from September 2004 to August 2008, due to cancer of the esophagus or cardia, from the fifth postoperative month. The operations were performed by the Group of Esophagus, Stomach and Duodenum Surgery of the Clinics Hospital of the Faculty of Medical Sciences, University of Campinas (UNICAMP), according to the standardized transmediastinal technique, followed by esophagogastroplasty with gastric tube, cervical esophagogastric anastomosis, pyloromyotomy and feeding jejunostomy in all cases.

This research was developed to meet the requirements of Resolution MS/CNS No 196 of October 10^th, 1996, and was approved by the Ethics and Research Committee of FCM-UNICAMP, with Protocol 505/2003 on 20/07/2004.

As inclusion criteria, we selected patients who were not undergoing chemo or radiotherapy and had no metastasis at the time of the study. No patient had verbalizing or memory difficulty to answer questions and all agreed to sign an Informed Consent Informed.

We did not include patients submitted to esophagectomy for benign disease, in the immediate postoperative period or in less than five months, bedridden and those who could not attend the clinic for evaluations.

Patients were asked, via social worker, to attend to the clinic on the date established to respond to the SF-36 questionnaire and physical examination, and recording of medical history, socio-economic and cultural data and clinical symptoms.

The data analyzed were age, sex, marital status, race, education, histological type, time elapsed between the operation and the interview, weight and height to calculate body mass index (BMI) obtained in balance platform, with the individual barefoot and wearing light clothing. The results of BMI were assessed according to the World Health Organization¹² for adults and to Lipschitz¹³ for elders.

Weight loss was calculated by analyzing the percentage of adequacy between the regular or usual weight of the patient before the operation and the current. The presence of dysphagia, difficulty chewing, anorexia, nausea, vomiting, diarrhea and constipation were investigated during the interview with the patient.

The quality of life was assessed by the questionnaire "Medical Outcomes Study 36-Item Short Form Health Survey" (SF-36) used in clinical practice in general, in research, evaluation of health policies and population analyzes to measure general quality of life. This questionnaire was developed by Ware and Sherbourne¹⁴ and translated into Portuguese and validated by Ciconelli et al.¹⁵.

The SF-36 consists of 11 sections with sub-items totaling 36 questions spread across eight domains. These areas are grouped into two major components: physical and mental.

The physical component involves the domains functional capacity, role physical aspects, pain and general health, while the mental component comprises the domains mental health, vitality, emotional and social aspects. The results obtained are compared with those of Aaronson et al.¹⁶.

The results from the SF-36 questionnaire of quality of life indicate better results when closer to 100 and worse outcomes when closer to zero.

Due to the characteristics of the disease, the sample size was established according to the availability of patients in the period studied, the occurrence of death, loss to follow-up and reflection on the practical aspects, such as time constraints and statistical issues. We used the absolute (n) and relative (%) frequencies for nominal qualitative variables, and the mean and standard deviation for quantitative variables and to describe the values found.

The Student t test was applied to the study of mean BMI of each histological type and to comparisons of the results obtained in the domains "Pain", "General Health" and "Mental Health", and the Mann-Whitney test for domains "Functional Capacity", "Limitation due to physical aspects", "vitality", "Social Aspects" and "Limitation due to Emotional Aspects".

The search for association between the time elapsed after the operation until the interview and the results of the assessment of quality of life was performed by Pearson correlation test. Furthermore, it was assessed whether the time elapsed from operation until the interview influenced the results of the quality of life of patients interviewed. The comparison between the mean obtained for each histological type was performed by the Mann-Whitney test.

The testes of association of anorexia, dysphagia, nausea/vomiting, bowel habits and the histological type were performed by Fisher's test. Significance was considered if "p" was less than 0.05.

RESULTS

The 24 study participants were mostly men (91.7%), Caucasian (70.8%), married (83.3%), mean age 58.8 years, minimum 44 and maximum 83 years . It is worth noting that 37.5% were elderly, or older than 60 years. Regarding education, the mean for this sample was 4.9 years studied (Table 1).

Patients eligible for the study were divided into two groups according to histological type: Adenoca (n = 10) and SCC (n = 14). All patients were evaluated with a minimum of five months postoperatively and a maximum of eight years, 11 months and four days. The mean postoperative time for survey participants was two years, four months and 26 days and, according to histological type, in cases of Adenoca the average time was one year, eight months and five days, and for SCC, two years, ten months and 31 days. However, this difference in time between the two histological types was not significant (p = 0.8168).

The distribution of variables "quality of life" and "time elapsed from operation" can be seen in figure 1.

Table 2 shows the values of the components of the SF-36 scores obtained and related to the time elapsed from operation.

The average percentage of weight loss (Table 3) was higher among patients with Adenoca (16.84%). However, the mean current BMI for the Adenoca group was 21.5 (SD 2.7) and in the SCC group it was 21.0 (SD-2, 8), without significant difference between the results (p = 0 , 6602).

When comparing the quality of life of both histological types of esophageal cancer, there was no significant difference in the domain "Functional Capacity", and all other areas were equal.

By analyzing the responses collected in the eight components of the SF-36 that were presented in Table 4, it can be said that there is a difference between the two histological types for the domain "Functional Capacity" (p = 0.017) and that for all other domains, equality cannot be rejected, and in the domains "Pain", "vitality", "Mental Health" and "Limitation due to Emotional Aspects", there is strong evidence for equality between the histological types.

The result obtained in the domain "Social Aspects" shows an average slightly different between the two histological types, but not considered significant (p = 0.2570), the same happening to "General Health" (p = 0.3591 ), "Limitation due to Physical Aspects" (p = 0.3614) and "Limitation due to Emotional Aspects" (p = 0.7317).

The domains "Limitations by Emotional Aspects" and "Limitation due to Physical Aspects" have the highest standard deviation among all categories, with the average component "Limitation due to Emotional Aspects" 20 points higher than the average of the variable "Limitation due to Physical Aspects".

Correlation analysis between the variable "Mental Health" and "Limitation due to Emotional Aspects" has resulted in ñ = 0.587, with a p-value of 0.003, and a strong evidence that there is a relationship between the two variables. Similar results were obtained in the variables "Limitation due to Physical Aspects" and "Pain", (ñ = 0.586, p=0.003). In addition, when analyzing the correlation of these variables between patients with Adenoca and SCC separately, the correlation was even greater.

The results obtained from the 24 patients studied after administration of the SF-36 are included in Table 4. Statistical analysis using the Fisher exact test showed no statistically significant differences in the pain domain (p = 0.032) for the group Adenoca and functional capacity (p = 0.003), Limitation due to physical aspects (p = 0.027) and in social aspects (p = 0.0468) for the SCC group.

The analysis of clinical data shows that there was no association between dysphagia, anorexia, nausea, vomiting, diarrhea and constipation and histological type (Table 5). Dysphagia was reported by 83.3% of patients and remains a major postoperative symptom, followed by anorexia (58.3%), nausea and vomiting (41.7%) and diarrhea (29.2%).

Other symptoms not related to postoperative esophagectomy were investigated and displayed percentages close to 42% for difficulty chewing and 25% for constipation.

DISCUSSION

The focus of this study was to compare the quality of life of patients submitted to esophagectomy for two histological types of esophageal cancer: the Adenoca of esophagus or cardia and SCC. The increasing frequency of Adenoca justifies this concern^17-20. Another issue to consider is the most pronounced increase in survival of patients with esophageal Adenoca when compared to patients with SCC, according to a study conducted in Sweden in the nineties²¹.

The SF-36 has been validated and used worldwide to evaluate patients with benign and malignant diseases, pre and postoperatively^14,15,22. And it was very useful in this population, since 79% of interviewed patients had some degree of functional illiteracy. The use of a visual scale that could be used in these situations to corroborate the results presented would contribute to obtain information more easily. Moreover, since it is a transversal study, during the research inevitable deaths occurred; this difficulty was also reported by other authors⁸.

The strong point of this study was to compare our results with the data presented by Aaronson et al.¹⁶ for a healthy Netherlands population, demonstrating significant differences in the pain domain (p = 0.032) for the Adenoca group, and functional capacity (p = 0.003), Limitation due to physical aspects (p = 0.027) and social aspects (p = 0.0468) for the SCC group.

The quality of life of patients with Adenoca showed similar results with the healthy population, according to research from De Boer et al.⁹, with the exception of pain domain, which differed from the healthy population. Zieren et al.²³ demonstrated that the quality of life of patients undergoing esophagectomy for SCC proved to be hampered by physical limitations.

In this research, the lowest scores were found in "Limitation due to Physical Aspects" and "Limitation due to Emotional Aspects". The lowest scores in these areas mean that the patients had problems with work or other daily activity depending on their physical and emotional health. These considerations were confirmed by the correlation found between the domains "Mental Health" and "Limitation due to Emotional Aspects" and "Limitation due to Physical Aspects" and "Pain" for all patients in general and also according to the histological type. And the best result for the histological type Adenoca in the domain "Functional Capacity" suggests that these patients are more likely than the others to perform all kinds of physical activities, including the most vigorous ones. Moreover, considering that the average of component "Limitation due to Emotional Aspects" was 20 points higher than the average of the variable "Limitation due to Physical Aspects", we can conclude that, after esophagectomy, the patient's physical condition is a greater difficulty than the psychological one.

The analysis of quality of life of patients in this study, in different transversal points (from five months to more than eight years after surgery) did not show to have been influenced by time, ie there was not a relationship of dependence between them. These results are in agreement with the prospective study of Djärv et al., who included patients submitted to esophagectomy between six months and three years, with no difference in quality of life related to health after the operation²⁴.

The dispersion analysis (Figure 1) between the variables quality of life and the elapsed time after surgery until the time of the interview also showed no statistical difference (p> 0.05), therefore not influencing the final results of the research. However, we believe that this result should be interpreted with caution due to the small sample and because quality of life is a subjective and multidimensional measure, results needing to be validated in a larger sample.

No association was found between quality of life and dysphagia, difficulty in chewing, anorexia, nausea, vomiting, diarrhea and constipation, although these data have been reported in both histological types. The difficulty in chewing reported by 42% of patients may be due to the presence of elderly in 37% of the sample, for whom the adequacy of dental prostheses and oral health could minimize the problems reported.

Although esophagectomy for esophageal cancer has a high operative morbidity, it is considered the standard treatment for patients with resectable tumors without clinical contraindications^3,25. Knowing the quality of life of the patient and the points at which it can be improved will certainly help the patient and the healthcare team to decide the best treatment and how to face this new phase of life.

It is essential that patients undergoing esophagectomy receive postoperative behavioral and dietary counseling as part of their overall treatment. In this sense, the participation of a multidisciplinary team composed of nutritionists, physiotherapists and psychologists can help patients in their recovery. The role of the family in this confrontation contributed greatly according to the observations of Steinglass et al.²⁶ in their survey on quality of life in oncology, emphasizing the need to develop tools for family assessment.

In conclusion, this study showed better functional capacity in the Adenoca group when compared to the SCC group and equality between them in the other areas of assessment of quality of life. A comparison of these groups with a healthy population showed equality of life between healthy people and the Adenoca group, except for pain and worse outcomes for functional capacity when the healthy group is compared to the SCC group. Patients in both groups suffered from dysphagia, anorexia, difficulty chewing, nausea, vomiting, diarrhea and constipation, which were not related to quality of life.

REFERENCES

• 1. Corley DA, Buffler PA. Oesophageal and gastric cardia adenocarcinomas: analysis of regional variation using the Cancer Incidence in Five Continents database. Int J Epidemiol. 2001;30(6):1415-25.
• 2. Jankowski JA, Perry I, Harrison RF. Gastro-oesophageal cancer: death at the junction. BMJ. 2000;321(7259):463-4.
• 3. Tercioti Jr V, Lopes LR, Coelho Neto JS, Andreollo NA. New aspects of the neo-adjuvant therapy in esophageal squamous cell carcinoma. A review of medical literature. ABCD, Arq bras cir dig. 2009;22(1):33-40.
• 4. Steffen A, Schulze MB, Pischon T, Dietrich T, Molina E, Chirlaque MD, et al. Anthropometry and esophageal cancer risk in the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomarkers Prev. 2009;18(7):2079-89.
• 5. de Boer AG, van Lanschot JJ, van Sandick JW, Hulscher JB, Stalmeier PF, de Haes JC, et al. Quality of life after transhiatal compared with extended transthoracic resection for adenocarcinoma of the esophagus. J Clin Oncol. 2004;22(20):4202-8.
• 6. Cense HA, Visser MR, van Sandick JW, de Boer AG, Lamme B, Obertop H, et al. Quality of life after colon interposition by necessity for esophageal cancer replacement. J Surg Oncol. 2004;88(1):32-8.
• 7. Blazeby JM, Farndon JR, Donovan J, Alderson D. A prospective longitudinal study examining the quality of life of patients with esophageal carcinoma. Cancer. 2000;88(8):1781-7.
• 8. Rosmolen WD, Boer KR, de Leeuw RJ, Gamel CJ, van Berge Henegouwen MI, Bergman JJ, et al. Quality of life and fear of cancer recurrence after endoscopic and surgical treatment for early neoplasia in Barrett's esophagus. Endoscopy. 2010;42(7):525-31.
• 9. De Boer AG, Genovesi PI, Sprangers MA, Van Sandick JW, Obertop H, Van Lanschot JJ. Quality of life in long-term survivors after curative transhiatal oesophagectomy for oesophageal carcinoma. Br J Surg. 2000;87(12):1716-21.
• 10. McLarty AJ, Deschamps C, Trastek VF, Allen MS, Pairolero PC, Harmsen WS. Esophageal resection for cancer of the esophagus: long- term function and quality of life. Ann Thorac Surg. 1997;63(6):1568-72.
• 11. Kirby JD. Quality of life after oesophagectomy: the patients' perspective. Dis Esophagus. 1999;12(3):168-71.
• ¹²
  OMS. El estado físico: uso e interpretación de la antropometria. Informe de un comité de Expertos de la OMS. Serie de informes técnicos 854. Genebra: OMS; 1993.
• 13. Lipschitz DA. Screening for nutritional status in the elderly. Prim Care. 1994;21(1): 55-67.
• 14. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992;30(6):473-83.
• 15. Ciconelli RM, Ferraz MB, Santos W, Meinão I, Quaresma MR. Tradução para a lingua portuguesa e validação do questionário genérico de avaliação de qualidade de vida SF-36 (Brasil SF-36). Rev Bras Reumatol. 1999;39(3):143-50.
• 16. Aaronson NK, Muller M, Cohen PD, Essink-Bot ML, Fekkes M, Sanderman R, et al. Translation, validation, and norming of the Dutch language version of the SF-36 Health Survey in community and chronic disease populations. J Clin Epidemiol. 1998;51(11):1055-68.
• 17. Jung KW, Talley NJ, Romero Y, Katzka DA, Schleck CD, Zinsmeister AR, et al. Epidemiology and natural history of intestinal metaplasia of the gastroesophageal junction and Barrett's esophagus: a population-based study. Am J Gastroenterol. 2011;106(8):1447-55.
• 18. Modena SF, Meirelles LR, Araujo MR. Are the nitrites important in a Genesis of the adenocarcinoma associated to the Barrett esophagus? ABCD, Arq Bras Cir Dig. 2008;21(3):124-9.
• 19. Cooper GS, Yuan Z, Chak A, Rimm AA. Association of prediagnosis endoscopy with stage and survival in adenocarcinoma of the esophagus and gastric cardia. Cancer. 2002;95(1):32-8.
• 20. Schembre D, Arai A, Levy S, Farrel-Ross M, Low D. Quality of life esophagectomy and endoscopic therapy for Barrett's esophagus with dysplasia. Dis Esophagus. 2010;23(6):458-64.
• 21. Sundelöf M, Ye W, Dickman PW, Lagergren J. Improved survival in both histologic types of oesophageal cancer in Sweden. Int J Cancer. 2002;99(5):751-4.
• 22. Brown LF, Kroenke K, Theobald DE, Wu J. Comparison of SF-36 vitality scale and Fatigue Symptom Inventory in assessing cancer-related fatigue. 2011;19(8):1255-9.
• 23. Zieren HU, Jacobi CA, Zieren J, Müller JM. Quality of life following resection of oesophageal carcinoma. Br J Surg. 1996;83(12):1772-5.
• 24. Djärv T, Lagergren J, Blazeby JM, Lagergren P. Long-term health-related quality of life following surgery for oesophageal cancer. Br J Surg. 2008;95(9):1121-6.
• 25. Tercioti Júnior V, Lopes LR, Coelho Neto Jde S, Carvalheira JB, Andreollo NA. Eficácia local e complicações da terapêutica neoadjuvante no carcinoma epidermoide: radioterapia versus radioterapia associada à quimioterapia. Rev Col Bras Cir. 2011;38(4):227-34.
• 26. Steinglass P, Ostroff JS, Steinglass AS. Multiple family groups for adult cancer survivors and their families: a 1-day workshop model. Fam Process. 2011;50(3):393-409.

Publication Dates

• Publication in this collection
  04 Apr 2013
• Date of issue
  Feb 2013

History

• Received
  25 May 2012
• Accepted
  30 July 2012