Abstract
The safety and feasibility of D2 lymphadenectomy for gastric cancer in Western patients have been shown by Italian Gastric Cancer Study Group (IGCSG). In our center at Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), we have been doing D1 lymphadenectomy all these years. Hence, this study was taken up to assess the feasibility of gastrectomy with D2 lymphadenectomy in patients with gastric cancer at JIPMER, Puducherry, India. Of the 148 carcinoma stomach patients explored, a total of 52 patients (35.13%) underwent resection with D1 (34 patients) or D2 (18 patients) lymphadenectomy, who formed the study groups. Patients were admitted and investigated by upper gastrointestinal endoscopy (UGIE) and other appropriate investigations including contrast-enhanced computed tomography (CECT) of the abdomen. Eligible patients had no serious comorbid cardiorespiratory disease that would preclude a safe D2 procedure. Two-third of the patients in both the groups belonged to the 50–75 age group. The mean number of nodes dissected was 6.44 ± 5.3 in the gastrectomy with D1 lymphadenectomy group versus 21.67 ± 5.3 in the gastrectomy with D2 lymphadenectomy group. There was no difference in the intraoperative blood loss, the number of units of blood transfused and the duration of surgery between D1 and D2 lymphadenectomy in our study. There was no difference between the postoperative stay and overall stay between the D1 and D2 lymphadenectomy. There was no significant difference between the overall morbidity and mortality or when the surgical complications were analysed individually. Intraoperative blood loss, the number of units of blood required for transfusion and the duration of surgery were not increased in D2 lymphadenectomy. The number of lymph nodes harvested was significantly more in D2 lymphadenectomy that resulted in a better staging. Postoperative morbidity or mortality in patients undergoing D2 lymphadenectomy was the same as in D1 lymphadenectomy. Hence, gastrectomy with D2 lymphadenectomy could be done safely.
Keywords: Gastric cancer, D1 lymphadenectomy, D2 lymphadenectomy, Morbidity, Mortality
Background
Carcinoma stomach is the fifth most common cancer in the world [1]. It is the third most common cause of cancer mortality worldwide [1]. In India, it is the fifth most common cancer in males and seventh in females [2, 3]. Estimates of 2012 show globally the highest incidence rates for both sexes were in Eastern Asia (35.4 and 13.8 per 100,000 in males and females, respectively) and the lowest in Western Africa (3.3 and 2.6 per 100,000 in males and females, respectively). The highest mortality rates were in Eastern Asia (24/100,000 for males and 9.8/100,000 for females) and lowest in North America (2.8 and 1.5 per 100,000, respectively in males and females) [1]. All though multidisciplinary management involved in reducing its high mortality rates, surgical resection remains the prime option [4].
Locally, advanced stomach cancer is most often treated by gastrectomy with D2 lymphadenectomy in the Far East [5–7]. It involves removing of D1 group nodes (perigastric) and left gastric, common hepatic, coeliac, hepatoduodenal, splenic hilar and nodes along splenic artery [8, 9]. Splenectomy or pancreatectomy is the reason behind increased mortality and morbidity following D2 lymphadenectomy in the West [10, 11].
Gastric cancer spreads through the rich plexus of lymphatics to local or regional lymph nodes. Despite this, it remains as a locoregional disease for a long time and only in its very advanced stages it spreads via the blood stream to other distant organs such as the liver, lungs or bones. This forms the basis of gastrectomy with D2 lymphadenectomy [12]. Gastric cancer in its early stages may be amenable to cure by the classical surgical methods of resection as suggested by Appleby and popularized by our Japanese colleagues [9].
Italian Gastric Cancer Study Group (IGCSG) showed D2 lymphadenectomy is safe and feasible in Western patients with gastric cancer [13]. In our center at JIPMER, we have been doing D1 lymphadenectomy all these years. Hence, this study was taken up to assess the feasibility of gastrectomy with D2 lymphadenectomy in patients with gastric cancer at JIPMER, Puducherry, India.
Methods
This was a prospective observational study done in the Department of Surgery, JIPMER, Puducherry, India from September 2011 to August 2013. The study was approved by the Institute Ethics committee. All the patients who attended the surgical clinic with suspected carcinoma of the stomach were investigated by upper gastrointestinal endoscopy (UGIE) and other appropriate investigations including contrast-enhanced computed tomography (CECT) of the abdomen. Eligibility criteria included those with histologically proven gastric adenocarcinoma, those not requiring emergency surgery, those planned for distal/total gastrectomy, in which preoperative clinical examination/imaging indicated operable disease, age less than or equal to 75 years and in good physical condition with no comorbid cardiorespiratory disease. Those patients were excluded from the study if they had previous gastric surgery, those who had coexisting cancer, those medically unfit for major surgery, and those aged >75 years, those who received pre-operative chemotherapy/chemo radiation and those with inoperable disease, peritoneal deposits, and para-aortic nodes. Patients having gastro-esophageal junction tumours were also excluded from the study. Preoperative workup was done and informed consent was obtained. Patients fulfilling the above inclusion criteria underwent laparotomy and intraoperatively assessed for D2 lymphadenectomy and if feasible underwent D2 Lymphadenectomy.
The Japanese Classification of Gastric Carcinoma, Third English Edition, was used for the anatomical description of lymph node stations and grouping, and the extent of gastric resection [14]. Following Japanese Gastric Cancer Association guidelines, when proximal edge of the tumour was more than 3 cm from the cardia in well-circumscribed (Borrmann type1 and type2) advanced cancers, or more than 6 cm in Borrmann type 3 cancers, distal gastrectomy was done. Since in our institution the terminology of subtotal gastrectomy and partial gastrectomy is being used for many years, distal subtotal gastrectomy was used when the distal resection removed two thirds or more of the stomach and distal partial gastrectomy when the distal resection removed less than two thirds of the stomach. This was necessary for comparison between the units. When these conditions were not met, total gastrectomy was done. Lymph node dissections (D1 and D2) were carried out accordingly to the given definition. Alimentary tract reconstruction was done by anterior gastrojejunostomy, and a nasogastric tube insertion across the anastomosis using 16 Fr Ryle’s tube was used for early feeding, and in few other cases, an additional feeding jejunostomy (FJ) was done along with gastrojejunostomy. In cases of total gastrectomy, Roux-en-Y esophagojejunostomy was done. The amount of intraoperative blood loss, the number of units of blood transfused intraoperatively and duration of surgery were noted.
The pathological examination of the surgical specimen was carried out by one of the consultants in pathology. The seventh edition of the American Joint Committee on Cancer Classification (AJCC) was used for staging cancer in the present study. Postoperative morbidity, if any, was noted. Patients were followed up postoperatively up to a month and later at regular intervals till the end of the study period for early recurrence. Imaging studies like ultrasonography/computed tomography/GI radiography, as well as endoscopy were done to confirm recurrence. At least one imaging was done during the study. The postoperative course including all complications, both surgical and non-surgical and reoperations was documented. Death during the patient’s hospital stay or within 30 days of the procedure was considered as in-hospital mortality.
As gastrectomy with D2 lymphadenectomy for gastric cancer was not done at JIPMER before this study, after the ethics committee clearance, gastrectomy with D2 lymphadenectomy was started by a single surgical unit. During the study, five cases were also done by other two surgeons who learned the technique of D2 lymphadenectomy. During the period of study, those patients in whom gastrectomy with D1 lymphadenectomy alone was done in all the surgical units were taken as the control for comparison.
Statistical Analysis
Statistical analysis was done by using SPSS 19.0 software version for windows. All the categorical data related to the patient’s baseline characteristics like gender, age, tumour location, tumour histology, type of surgery, TNM staging, and complications were presented as frequencies and percentages. Chi-square test was used to compare the proportions and percentages. All normally distributed continuous data like number of lymph nodes dissected, duration of hospital stay, amount intraoperative blood loss, the number of units of blood transfused intraoperatively and duration of surgery was presented as mean with standard deviation and range. Independent Student’s t test was used to compare the continuous variables between the groups. All statistical analysis was carried out for two-tailed significance and the P value <0.05 was considered as significant.
Results
From September 2011 to August 2013, a total of 163 patients with carcinoma stomach were admitted in the Department of Surgery, JIPMER, Puducherry, India. Of these, 15 patients did not undergo surgery. Eleven patients had metastatic disease, three patients went against medical advice and one patient had an acute exacerbation of asthma, hence could not undergo surgery. Remaining 148 (90.79%) patients underwent exploratory laparotomy. It can be seen that most of the patients underwent either palliative gastrojejunostomy (51, 34.5%) or resection with D1 lymphadenectomy (34, 23%). Only 18(12.2%) could undergo gastrectomy with D2 lymphadenectomy (Table 1). Those patients who underwent gastrectomy with D2 lymphadenectomy or D1 lymphadenectomy were grouped for comparison. The groups were comparable with respect to age, sex, tumour location and histology (Table 2).
Table 1.
Details of 148 exploratory laparotomies for gastric cancer at JIPMER hospital (September 2011–August 2013)
| S. no. | Procedure done | n (%) |
|---|---|---|
| 1. | Exploratory laparotomy only (unresectable disease) | 23 (15.5) |
| 2. | Feeding jejunostomy (FJ) | 17 (11.5) |
| 3. | Palliative gastrojejunostomy (Palliative GJ) | 51 (34.5) |
| 4. | Palliative gastrectomy | 5 (3.4) |
| 5. | D2 lymphadenectomy | 18 (12.2) |
| 6. | D1lymphadenectomy | 34 (23.0) |
Table 2.
Demography and other characteristics of the two study groups
| Parameter | D1 gastrectomy (n = 34) | D2 gastrectomy (n = 18) | p value |
|---|---|---|---|
| Sex ratio (M:F) | 19:15 | 11:7 | 0.717 |
| Mean (range) age (years) | 54.6 ± 13.30(30–75) | 53.8 ± 11.62 (30–75) | 0.822 |
| Age 50–75 years | 21 (61.8) | 12 (66.7) | |
| Tumour location | |||
| Antropyloric | 32 (94.1) | 13 (72.2) | 0.028 |
| Mid body | 2 (5.9) | 3 (16.7) | 0.209 |
| Proximal body | 0 (0.0) | 2 (11.1) | 0.047 |
| Type of resection | |||
| Distal-partial gastrectomy | 17 (50.0) | 8 (44.4) | 0.703 |
| Distal-subtotal gastrectomy | 15 (44.1) | 4 (22.2) | 0.119 |
| Total gastrectomy | 2 (5.9) | 6 (33.3) | 0.009 |
| Tumour histology | |||
| Intestinal | 22 (64.7) | 13 (72.2) | 0.583 |
| Diffuse | 11 (32.4) | 5 (27.8) | 0.734 |
| Mixed | 1 (2.9) | 0 (0.0) | 0.463 |
| Tumour stage | |||
| pT1a | 1(2.9) | 0(0.0) | 0.463 |
| pT1b | 0(0.0) | 1(5.6) | 0.165 |
| pT2 | 12(35.3) | 9(50.0) | 0.304 |
| pT3 | 11(32.4) | 7(38.9) | 0.637 |
| pT4a | 10(29.4) | 1(5.6) | 0.045 |
| TNM stage | |||
| IA | 1(2.9) | 0(0.0) | 0.463 |
| IB | 7(20.6) | 1(5.6) | 0.153 |
| IIA | 7(20.6) | 4(22.2) | 0.891 |
| IIB | 8(23.5) | 1(5.5) | 0.103 |
| IIIA | 7(20.6) | 8(44.4) | 0.071 |
| IIIB | 1(2.9) | 4(22.2) | 0.025 |
| IIIC | 3(8.8) | 0(0.0) | 0.194 |
| No. of lymph nodes dissected | |||
| Mean ± S. D. | 6.44 ± 5.34 | 21.67 ± 5.30 | 0.01 |
| Range | 0–23 | 14–36 | |
| Node stage | |||
| pN0 | 15(44.1) | 3(16.7) | 0.048 |
| pN1 | 9(26.5) | 1(5.6) | 0.069 |
| pN2 | 7(20.6) | 5(27.8) | 0.558 |
| pN3 | 3(8.8) | 9(50.0) | 0.001 |
Values in parentheses are percentages unless indicated otherwise
pN pathological node metastasis, pT pathological tumour stage
D2 lymphadenectomy was done in the majority when the tumour was located in the antro-pyloric region than in proximal body (72.22 vs 11.11%) (Table 2). Seventeen of 34 patients (50.00%) in the D1 lymphadenectomy group and 8 of 18 patients (44.44%) in the D2 lymphadenectomy group underwent a distal partial gastrectomy. Total gastrectomy was done in 2 of 34 patients (5.88%) and 6 of 18 patients (33.33%) in the D1 and D2 lymphadenectomy groups respectively. This was statistically significant between the study groups (P = 0.009). The mean number of nodes dissected was 6.44 ± 5.3 (range 0–23) in the gastrectomy with D1 lymphadenectomy group versus 21.67 ± 5.3 (14–36) in the gastrectomy with D2 lymphadenectomy group. This was statistically significant (p = 0.01) (Table 2). Overall 34 of 52 (65.38%) patients studied had nodes positive for metastasis (Table 2).
There was no difference in the intraoperative blood loss, blood transfusion and duration of surgery. The postoperative period or the total duration of stay was not prolonged in the D2 group (Table 3).
Table 3.
Intraoperative blood loss, number of units of blood transfused and duration of surgery and hospital stay
| Parameter | D1 gastrectomy mean ± S.D.(range) | D2 gastrectomy mean ± S.D.( Range) | p value |
|---|---|---|---|
| Intraoperative blood loss (ml) | 417.7 ± 305.0 (200–2000) | 363.9 ± 113.5 (200–600) | 0.475 |
| Units of blood transfused (Intraoperative) | 0.74 ± 0.71 (1–3) | 0.56 ± 0.61 (0–2) | 0.368 |
| Duration of surgery (hours) | 4.00 ± 0.71 (2.5–5.5) | 3.81 ± 1.13 ( 2–6.5) | 0.448 |
| Postoperative stay(days) | 14.8 ± 9.7 (8–50) | 16.7 ± 6.8 (9–35) | 0.456 |
| Total duration of stay(days) | 25.8 ± 11.4 (11–54) | 25.7 ± 9.4 (14–43) | 0.974 |
Table 4 summarizes postoperative complications. There was no statistical significance seen in the non-surgical and surgical complications between the study groups except that two patients in gastrectomy with D2 lymphadenectomy had significant hyponatremia. Splenectomy had to be done in 1 of 34 patients (2.94%) in the gastrectomy with D1 lymphadenectomy group due to splenic injury but not done in any of the patients in D2 lymphadenectomy group (p = 0.463). There was no mortality in patients undergoing D2 lymphadenectomy.
Table 4.
Postoperative complications
| Parameter | D1gastrectomy n (%) | D2 gastrectomy n (%) | p value |
|---|---|---|---|
| Non-surgical complications | 10 (29.4) | 6 (33.3) | |
| SSI | 7 (20.6) | 4 (22.2) | 0.891 |
| CCF | 1 (2.9) | 0 (0.0) | 0.294 |
| Pleural effusion | 1 (2.9) | 0 (0.0) | 0.294 |
| Hyponatremia | 0 (0.0) | 2 (11.1) | 0.047 |
| Hemiparesis | 1 (2.9) | 0 (0.0) | 0.463 |
| Surgical complications | 3(8.8) | 6 (33.3) | |
| Duodenal stump leak | 3 (8.8) | 4 (22.2) | 0.178 |
| Adhesive intestinal obstruction | 0 (0.0) | 1 (5.6) | 0.165 |
| Bleeding | 0 (0.0) | 1 (5.6) | 0.165 |
SSI surgical site infection, CCF congestive cardiac failure
Table 5 shows the comparison of the short-term out come in the study groups. Patients in gastrectomy with D2 lymphadenectomy group had a significantly more surgical complication, but when the surgical complications like duodenal leak, bleeding and postoperative adhesive obstruction were analysed separately, there was no difference. Also, there was no statistical significance in overall morbidity and mortality between the groups.
Table 5.
Short-term outcome
| Parameter | D1gasrectomy n (%) | D2gastrectomy n (%) | p value |
|---|---|---|---|
| Surgical complications | 3 (8.8) | 6 (33.3) | 0.02 |
| Non-surgical complications | 10 (29.4) | 6 (33.3) | 0.771 |
| Total morbidity | 10 (29.4) | 10 (55.6) | 0.065 |
| Postoperative/30-day mortality | 1 (2.9) | 0 (0.0) | 0.463 |
Table 6 shows follow-up of patients. The duration of follow-up was comparable. The majority of the patients in both the groups received adjuvant chemoradiotherapy (25 of 33 patients, 75.75% in gastrectomy with D1 lymphadenectomy vs. 7 of 18 patients, 38.88% in the gastrectomy with D2 lymphadenectomy group). Complications during follow-up were comparable between the groups. Two of 33 patients (6.06%) in D1 lymphadenectomy group and 1 of 18 (5.55%) patients in gastrectomy with D2 lymphadenectomy group had a recurrence and died. None of the patients in both the groups were lost to follow-up.
Table 6.
Follow-up of 51 patients
| Parameters | D1gastrectomy n (%) | D2 gastrectomy n (%) |
|---|---|---|
| Duration of follow-up(months) | ||
| Mean | 11.9 | 8.9 |
| Range | 2–22 | 3–21 |
| Concurrent chemoradiotherapy | 25 (75.8) | 7 (38.9) |
| Adjuvant radiotherapy only | 0 (0.0) | 2 (11.1) |
| Adjuvant chemotherapy only | 2 (6.1) | 1 (5.6) |
| Not fit for chemoradiotherapy | 5 (15.2) | 1 (5.6) |
| Only on follow-up | 1 (3.0) | 7 (38.9) |
| Complications during follow-up | ||
| Adhesive intestinal obstruction | 1 (3.0 ) | 2 (11.1 ) |
| Diarrhoea | 1 (3.0 ) | 1 ( 5.6) |
| Recurrence during follow-up | 2 (6.1) | 1 (5.6) |
| Recurrence period | ||
| 5 months | 0 (0.0) | 1 (5.6) |
| 9 months | 1 (3.0) | 0 (0.0) |
| 18 months | 1 (3.0) | 0 (0.0) |
| Died during follow-up | 11 (33.3) | 2 (11.1) |
| Time of death during follow-up | ||
| 3 months | 3 (9.1) | 0 (0.0) |
| 6 months | 0 (0.0) | 2 (11.1) |
| 9 months | 3 (9.1) | 0 (0.0) |
| 12 months | 3 (9.1) | 0 (0.0) |
| 22 months | 2 (6.1) | 0 (0.0) |
| Total deaths during study period | 12 (35.3) | 2 (11.1) |
| Lost follow up | 0 | 0 |
| Total patients followed up | 33 (100) | 18 (100) |
Discussion
The controversy regarding the extent of lymphadenectomy in gastric cancer continues till today because of its impact on survival. It was shown by the retrospective studies (prospectively maintained database) from Japan that extensive lymphadenectomy for gastric cancer can be done safely and is associated with increased survival [15, 16]. This was questioned by the randomized trials from the west, which showed increased morbidity and mortality associated with D2 lymphadenectomy [17–21]. But when these randomized trials were re-analysed, it was noticed that excessive morbidity and mortality was due to inadequate training of the surgeons, concomitant splenectomy and pancreatectomy [22–29]. It was shown by the subset analysis and also by adequate training that D2 gastrectomy can be done without increased morbidity and mortality by avoiding splenectomy and pancreatectomy [13, 24]. Increased survival of those who undergo D2 lymphadenectomy is also confirmed by prospective studies [25, 30–32].
Hence, this study was undertaken by us to see the feasibility of doing D2 lymphadenectomy in our department. It may be noted from the data that two-third of the patients had an inoperable disease at presentation which was the reason for the attitude of the surgeons continuing to do gastrectomy with D1 lymphadenectomy in our center. D2 lymphadenectomy with gastrectomy, irrespective of the location of the tumour in the stomach was started in our institute by an experienced surgeon in one of the surgical units. Gastrectomies with D1 lymphadenectomy done in all the surgical units were taken as controls for comparison.
Following D2 lymphadenectomy, the number of lymph nodes harvested in this study was significantly higher. The mean number of nodes harvested in D2 lymphadenectomy was 21.67 ± 5.3 whereas it was 6.44 ± 5.3 in the case of D1 lymphadenectomy. Edward P et al. has reported similar results [33]. None of the patients in D2 lymphadenectomy group required splenectomy, but it was done in one patient with D1 lymphadenectomy.
In a study done by Degiuli M et al. [34], 48.1% of the patients in D1 lymphadenectomy and 43.5% in D2 lymphadenectomy were in the pN0 stage. Nodal metastasis was seen in 51.9% in D1 lymphadenectomy and 56.5% in D2 lymphadenectomy group. Only 6.1% in D1 lymphadenectomy and 8.4% in D2 lymphadenectomy were in the pN3 stage. In the present study, 15 of 34 patients (44.11%) in D1 lymphadenectomy group and 3 of 18 patients (16.66%) in the D2 lymphadenectomy group were in the pN0 stage. Overall, 34 of 52 (65.38%) patients studied had nodes positive for metastasis. Nine of 18 patients (50.00%) in the D2 lymphadenectomy group were in pN3 stage. This shows the advanced disease at presentation unlike in west.
There appeared to be a selection bias in gastrectomy with D2 lymphadenectomy during surgery, only one of the 18 had T4a stage tumour compared with 10 cases (29.4%) that underwent D1 lymphadenectomy. However following D2 lymphadenectomy, 50% of the patients had N3 nodal status compared with only 8.8% of cases of D1 lymphadenectomy. This resulted in a better staging of the patients who underwent D2 lymphadenectomy with the result, 66% of the patients in D2 lymphadenectomy having stage III disease compared with only 31% of D1 lymphadenectomy shown to be having stage III disease. In a study done by Songun I et al. [25], 41% in D1 lymphadenectomy group and 53% in the D2 lymphadenectomy group were in stage IA. Only 3% of the patients in D1 lymphadenectomy and 29% in the D2 lymphadenectomy were in stage IIIA and IIIB together. This shows that our patients usually present when the disease is fairly advanced.
In the studies done by Dent DM et al. [17] and Pacelli F et al. [35], patients who underwent extended lymphadenectomy had a longer operating time, greater intraoperative blood transfusion requirement and more reoperation rate than those underwent limited dissection. There was no difference in the intraoperative blood loss, the number of units of blood transfused and the duration of surgery between D1 and D2 lymphadenectomy in our study. There was no difference between the postoperative stay and overall stay between the D1 and D2 lymphadenectomy in our study that was similar to the result of the study done by Degiuli M et al. [34].
Though there appeared to be a more surgical complication in D2 lymphadenectomy group in the form of duodenal stump leak, bleeding or adhesive obstruction, there was no significant difference seen between the overall morbidity or when the complications were analysed individually. This was similar to the results of Wu BuQiang et al. [28] who showed that the early morbidity of D2 dissection was higher than that of D1 dissection (20.6 vs. 39.6%, P < 0.05) but, there was no significant difference was observed (4.2 vs. 0, P > 0.05) when complications were analysed individually. This was supported by the two other studies done by Pacelli F et al. [35] and Degiuli M et al. [34].
In this study, the mortality rate in gastrectomy with D1 lymphadenectomy group was 2.94% but in D2 lymphadenectomy group there was none which was statistically significant. Pacelli F et al. [35], Edwards P et al. [33] and Degiuli M et al. [34] have observed that the in-hospital mortality rate was similar in the two groups. The results of these studies support the value of extensive lymph node dissection in the surgical treatment of gastric carcinoma.
Hence, it can be concluded that D2 lymphadenectomy can be done safely irrespective of the location of the tumour in the stomach. The amount of intraoperative blood loss, the number of units of blood required for transfusion and the duration of surgery are not increased in D2 lymphadenectomy. The number of lymph nodes harvested is significantly more which results in a better staging. Postoperative morbidity or mortality in patients undergoing D2 lymphadenectomy is the same as in D1 lymphadenectomy. Hence, D2 lymphadenectomy can be done safely in patients with resectable carcinoma of the stomach.
The present study had certain limitations. The study was carried out as a prospective observational study of gastrectomy with D2 lymphadenectomy in one surgical unit. Since gastrectomy with D1 lymphadenectomy was also being continued in all the surgical units, they were taken as the control group. There was no randomization. Since the study was planned over fixed time frame, sample size (N = 52) was limited. Assessment of curability by ruling out distant lymph node metastasis, by frozen section examination of the para-aortic lymph nodes or irrigated peritoneal fluid examination after laparotomy to detect free abdominal tumour cells was not done, which was another limitation.
Authors’ Contributions
Study design and methodology were done by Vishnu Prasad Nelamangala Ramakrishnaiah and Srinivasan Krishnamachari. Data collection and the review of literature were done by Ganesh Vadthya. Writing the results, discussion and conclusions were done by all the three authors.
Compliance with Ethical Standards
Conflicts of Interest
The authors declare that they have no conflict of interest.
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