Japanese Journal of Clinical Oncology Advance Access published online on November 8, 2008
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyn122
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© The Author (2008). Published by Oxford University Press. All rights reserved
Primary Adenocarcinoma of the Small Intestine: Presentation, Prognostic Factors and Clinical Outcome
1 Division of Medical Oncology, Department of Internal Medicine
2 Department of Surgery, The Catholic University of Korea College of Medicine, Seoul, Korea
For reprints and all correspondence: Sang Young Rho, Division of Medical Oncology, Department of Internal Medicine, Uijeongbu St Mary Hospital, College of medicine, Catholic University of Korea, 65-1 Kumoh-dong, Uijeongbu Kyonggi-do 480-130, Seoul, Korea. E-mail: ssuki76{at}catholic.ac.kr
Received June 10, 2008; accepted October 2, 2008
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Background: Malignant small intestine tumor accounts for 0.1–0.3% of all malignancies. Although primary adenocarcinoma is the most common histologic subtype, there is no report of the clinical characteristics and natural history in the Asian population.
Methods: We conducted retrospective analysis for the patients with the small intestine adenocarcinoma to explore the clinical characteristics and prognosis. All patients with adenocarcinoma of small intestine diagnosed between March 1997 and March 2007 in the Catholic Medical Center in Korea were identified through the cancer registry. The medical records were reviewed for patient characteristics, treatment and outcome data.
Results: Data on 53 patients were available. Twenty-six patients (49.0%) underwent curative resection and 13 patients receiving adjuvant chemotherapy. Fifteen patients received palliative chemotherapy. Median of overall survival of all patients was 12 months (95% confidence interval (CI): 8.5–15.1 months). Three-year survival and relapse-free survival rates after curative resection was 66.1 and 50.8%, respectively. Median survival of patients received palliative chemotherapy was 8.0 months (95% CI: 3.5–12.4).
Conclusions: The prognosis of primary adenocarcinoma of small intestine was poor, especially in cases where curative resection could not to be performed. Further study on the methods for early detection and effective systemic chemotherapy should be investigated.
Key Words: adenocarcinoma • small intestine • early detection • survival
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Malignant small intestine tumors are very rare and they account for 0.1–0.3% of all malignancies (1). Primary adenocarcinoma is the most common histologic subtype of carcinoma of the small bowel, and it makes up 25% of all small intestine tumors and 40% of all small intestine malignant tumors (2). The clinical characteristics, the treatment modalities and prognosis of this cancer are not well known because of its rarity.
The clinical presentation and diagnosis of this disease are usually delayed because small intestine adenocarcinoma is not amendable to endoscopic examination, and especially the disease that is distal to the duodenum (3). In terms of treatment, surgical intervention provides curative resection in 40–60% of these patients (4–7). There is a 5 year survival rate of 40–60% for resected tumors versus 15–30% for unresected tumors (4–7).
A recent annual report of the Korea central cancer registry stated that 449 new cases of small intestine adenocarcinoma occurred for 2002 (8) and projected incidence in the USA were 6170 cases for 2006 (9). Yet there are only case reports to date about the clinical presentation and treatment outcome of patients with small intestine adenocarcinoma in the Asian population. Therefore, we conducted a retrospective analysis of our 10 years’ experience at the Catholic Medical Center with primary small intestine adenocarcinoma.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Following approval of the Institutional Review Board, the patients with primary small intestine adenocarcinoma who were treated at St Mary's hospital, Kangnam St Mary's Hospital and Uijeongbu St Mary's Hospital between 1997 and 2007 were identified through the cancer registry. The patients’ records were reviewed retrospectively. The data were analyzed to determine the patients’ demographic distribution, the clinical presentation, disease stage, diagnostic methods, treatment and follow-up data, including the pattern of failure, the treatment response and survival. All patients had small intestine adenocarcinoma at the duodenum, ileum and jejunum and/or adenocarcinoma lesions of the small intestine not otherwise specified. Periampullary tumor and ampulla of vater tumor were excluded. The TNM stage of the American Joint Committee on cancer staging was used when available. The clinical staging was used when the pathologic staging was unavailable. The World Health Organization standard grading system with its four categories (well differentiated, moderately differentiated, poorly differentiated and undifferentiated) was used for the histologic grades.
Statistical Methods
The frequencies and descriptive statistics of the demographic and clinical variables were determined. Chi-square and Fisher exact tests were used for categorical variables and Student t-tests were used for the continuous and ordinal variables, as appropriate. Spearman's rank analysis was used to assess the correlations among the variables. The overall survival time was calculated from the date of diagnosis to the date of death or the last known follow-up. The relapse-free survival (RFS) time was calculated from the date of diagnosis to the first documentation of disease recurrence or death or the last known follow-up. The survival time was estimated using Kaplan–Meier methods. The log-rank test was used to compare the survival curve. The univariate and multivariate predictors of OS were determined by the Cox proportional hazard model. Rate ratios and their 95% confidence intervals (CIs) were calculated. The SPSS program for Windows (version 11.0; SPSS, Inc., Chicago, IL, USA) was used for analysis.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Patients Characteristics
Overall, 53 patients with primary small intestine adenocarcinoma were identified from the cancer registry. The baseline characteristics are summarized in Table 1. The median age was 63 years (range: 26–84 years). Thirty-two patients (60.4%) were
60 years, and 29 patients (54.7%) were male. The clinical presentation included abdominal pain in 38 (71.7%), abdominal distension in nine (17.0%), bleeding in three (5.7%) and jaundice in seven patients (13.2%). The clinical presentation did not differ according to the site of the primary tumor. The location of the primary tumor was the duodenum in 39 patients (73.6%), the jejunum in seven patients (13.2%) and the ileum in seven patients (13.2%). Tumor markers were evaluated in only 30 patients for the carcinoembryonic antigen (CEA) level and in 37 patients for the carbohydrate antigen (CA19-9) level. An elevated level of CEA (>4 ng/ml, normal range: 0–4 ng/ml) was noted in 15 patients (median: 4.16 ng/ml, range: 0–480 ng/ml) and an elevated level of CA19-9 (>34 U/ml, normal range: 0–34 U/ml) was noted in 16 patients (median: 23.4 U/ml, range: 0–8901 U/ml). All the patients with elevated tumor markers had more than Stage 2 disease, but elevated tumor markers did not correlate with the stage. In terms of diagnostic methods, upper gastrointestinal endoscopy established the diagnosis in 30 patients (56.6%) and the primary site for them was the duodenum. In contrast, distally located small intestine adenocarcinoma was diagnosed with laparotomy in 12 of 14 patients (85.7%) and two patients were diagnosed through computerized tomography.
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Pathologic Characteristics and Stage
The histologic grading was available for 53 patients. Of these patients, 16 patients (30.2%) had well-differentiated tumor, 21 patients (39.6%) had moderately differentiated tumor and 16 patients (30.2%) had poorly differentiated carcinoma (Table 2).
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In terms of the TNM staging, four patients (7.6%) had Stage 1 disease, 12 patients (22.6%) had Stage 2 disease, 15 patients (28.3%) had Stage 3 disease and 22 (41.5%) had Stage 4 disease (Table 2). Among patients with Stage 4 disease, eight patients (15.1%) had carcinomatosis, seven patients (13.2%) had liver metastasis and four patients (7.5%) had liver metastasis and carcinomatosis peritoni. One patient each had distant lymph node and lung metastases, respectively.
Treatment Modalities
The treatment modalities are summarized in Table 3. Among the 31 patients (58.5%) with localized disease, curative resection was performed in 26 patients (83.9%) and palliative bypass surgery or percutaneous biliary drainage was performed in five patients (16.1%). No patient died of postoperative complications. Among the 26 patients with curative resection, 13 patients received adjuvant therapy. In terms of the regimen of chemotherapy, five patients received a combination of 5-fluorouracil (5-FU) and cisplatin, four patients received 5-FU and leucovorin, three patients received 5-FU with concurrent chemoradiation therapy and one patient received the combination of 5-FU, doxorubicin and mitomycin. Thirteen (50%) of the 26 patients who received curative resection had recurrent disease. Among them, three patients received palliative chemotherapy. Among the 22 patients with metastatic disease, palliative chemotherapy was performed in 11 patients (50%) and palliative surgery alone such as bypass surgery (gastrojejunostomy) or percutaneous biliary drainage was performed in seven patients (31.8%). No treatment was performed in four patients (17.4%).
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In terms of palliative chemotherapy, overall 15 patients received palliative chemotherapy. Among them, 11 patients had metastatic disease at diagnosis, three patients had recurrent disease and one patient had localized disease, but he did not receive curative resection due to poor general medical condition. In terms of the regimens of chemotherapy, the most common regimen was a combination of 5-FU and cisplatin (eight patients). The others were a 5-FU-based regimen for two patients, oral capecitabine for two patients, a combination of epirubicin, cisplatin and 5-FU (the ECU regimen) for two patients and an irinotecan-based regimen for one patient. Five of these 15 patients received second-line palliative chemotherapy.
Survival
Among the 53 patients, 29 patients were followed until death, eight patients were alive without disease until the last follow-up and seven patients were followed until relapse. The median follow-up time was 12 months (range: 1–151 months). The median follow-up time among the patients who remained alive was 28 months (range: 2–151 months). The median OS time was 12 months, with a 95% CI of 8.9–15.1 months. The 3-year OS rate of all the patients was 44.1% (Fig. 1).
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Patient Characteristics and Survival
The median OS for the patients with an age <60 years did not reach the median and these patients’ OS tended to be associated with longer as compared with the patients with an age
60 years, although no statistically significant difference was detected (P = 0.056) (Table 4).
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Tumor Factors and Survival
The median OS of the patients with Stage IV disease was 4 months with a 95% CI of 2.6–7.6 months and this was significantly shorter than the survival of patients with Stage I–III disease (38 months) (log-rank test, P < 0.0001) (Fig. 2, Table 4).
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No statistically significant difference was detected for the OS according to the primary site of adenocarcinoma, although primary duodenal adenocarcinoma tended to be associated with a shorter median OS compared with the other primary sites (log-rank test, P = 0.056) (Table 4). However, 20 patients (90%) with Stage IV disease had primary duodenal adenocarcinoma.
In terms of the histologic grade, no statistically significant difference was detected, although the poorly differentiated tumor tended to be associated a shorter OS compared with the well and moderately differentiated tumor (log-rank test, 7 versus 13 months, P = 0.157) (Table 4).
In terms of the tumor markers, 16 (44.4%) of the 37 patients and 15 (50.0%) of the 30 patients had elevated levels of CA19-9 and CEA, respectively. The median OS of the patients with elevated tumor markers was 5 months with elevated levels of CA19-9 and CEA and this was significantly shorter than the survival of patients who did not have elevated tumor marker levels (log-rank test, P = 0.02).
Treatment Modalities and Survival
In terms of treatment modalities, the 3-year OS rate was significantly higher for the patients who underwent curative resection as compared with the patients who did not (66.1 versus 0%, respectively, log-rank, P < 0.0001) (Fig. 3). Three-year RFS rate after curative resection was 50.8%. The median RFS of the patients who received curative resection did not reach the median and in these patients, RFS was significantly longer as compared with patients who did not receive curative resection (5 months, P < 0.0001).
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Adjuvant chemotherapy after curative resection was associated with longer survival compared with curative resection alone, although no statistically significant difference was detected (P = 0.130). In terms of palliative chemotherapy, among the patients with metastatic disease (n = 22) or recurrent/locally advanced disease (n = 14), 15 patients (41.7%) received palliative chemotherapy. The palliative chemotherapy improved the OS compared with the patients who received no chemotherapy (a median OS of 8 versus 3 months, respectively, P = 0.025).
Independent Predictor of Survival
On univariate analysis, the presence of metastasis (Stages I–III versus Stage IV) and elevated tumor marker levels were significantly associated with OS (P < 0.001 and =0.02, respectively). None of the following was found to be significantly associated with OS: patient age (P = 0.056), gender (P = 0.725), the histological grade (P = 0.166) and the primary site of tumor (P = 0.056). All the variables that were statistically significant on univariate analysis were evaluated by Cox-regression analysis. Only the presence of metastasis remained significantly associated with OS (P < 0.001, relative risk = 8.93, 95% CI: 3.4–23.2).
Pattern of Failure
Among the 26 patients who received curative resection, 10 patients were alive without recurrence and 13 patients (50%) subsequently developed recurrence. Three patients were lost to follow-up. The median time to recurrence was 24 months (range: 5–58 months). Among them, four patients had local recurrence and nine patients recurred at distant sites. The sites of distant recurrence carcinomatosis (n = 5) were liver (n = 3) and bone (n = 1).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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The clinical characteristics, treatment modalities and prognosis of patients with adenocarcinoma of the small intestine are not well known because of the rarity of this cancer. Although it is the most common histologic subtype of small bowel malignancy, there have been no domestic reports on adenocarcinoma of the small intestine. Most previous series have evaluated fewer than 15 patients in subset analyses (9).
The Annual Report of the Korea Central Cancer Registry 2002 found that small intestine malignancies accounted for 0.5% of all malignancies (8). These tumors were most often present in patients aged 60–64 years, and there was no difference in gender distribution. Adenocarcinoma is the most common subtype of small intestinal malignancies, present in 31.2% of these patients (8). Of the 138 patients with small intestine malignancies identified from the cancer registry, 53 (38.4%) had been diagnosed with small intestine adenocarcinoma, in agreement with previous reports (2). Median patient age was 63 years, and 60.4% were more than 60-year old, in accordance with previous findings (10,11). The most common primary tumor site was the duodenum, as observed in 73.6% our patients, which is somewhat higher than the 52% observed in previous reports (10–12). The duodenum may be at highest risk of small intestine adenocarcinoma because it is the first site in the small intestine to be exposed to a variety of potentially injurious agents, such as bile, pancreatic secretions and stomach acid (13). In addition, the risk of duodenal adenocarcinoma is increased in patients with familial adenomatous polyposis (FAP) (14). Duodenal adenoma may develop in 24–100% of these patients, and an adenoma–carcinoma relationship has been reported for small bowel adenocarcinoma, similar to large bowel adenocarcinoma (14,15). The incidence of ileal adenocarcinoma is increased in patients with Crohn's disease (13,16). Although we could not evaluate what fraction of small intestine adenocarcinoma was derived from underlying disease, such as FAP or Crohn's disease, such factors may contribute to the distribution of the primary tumor site. However, ileal and jejunal adenocarcinomas may be missed when diagnosing small intestine adenocarcinoma because these primary sites are not amenable to endoscopic examination (3).
We observed a shorter median OS (12 months) than previously reported (10–12). Most series have consistently shown that the absence of distant metastasis and cancer-directed surgery were associated with improved survival (4,5,10–12). We found that 26 of the 31 patients (83.8%) with localized disease underwent cancer-directed surgery and that the median OS of these 31 patients was 38 months, a finding comparable with previous results. Dabaja et al. (12) reported that the cancer-directed surgery rate, the 5-year OS rate and median survival were 84%, 36 and 29 months, respectively. However, the proportion of our patients with Stage IV disease (41.5%) was higher than that in the earlier studies (29 and 34%, respectively) (11,12). Of our 22 patients who presented with metastatic disease, 11 (50.0%) received palliative chemotherapy and had a median OS of 5 months, in agreement with previous findings (11,12). The shorter survival we observed may have been due to the higher proportion of patients with Stage IV disease (11–13). Another possible reason for the worse outcome of the current study was that the proportion of duodenal adenocarcinoma was higher than that of previous reports. Patients with duodenal adenocarcinoma had poorer outcomes than patients with tumors at other primary sites. Patients with duodenal adenocarcinoma were found to present at more advanced stages and at older ages compared with patients with tumors at other primary sites (13). In addition, tumors at this site usually require surgery using Whipple's procedure, a complex procedure that has been associated with high patient mortality (13).
We found that 7.6, 22.6, 28.3 and 41.5% of our patients had Stages I, II, II and IV disease, respectively, a finding similar to that of the US National Cancer Institute database in 1995 (10). In patients with colorectal cancer, 23.1, 30.3, 25.2 and 19.4% present with Stages I, II, III and IV, respectively (17), indicating that patients with small bowel adenocarcinoma are diagnosed at a more advanced stage. At present, there are no good screening methods for small bowel adenocarcinoma. Moreover, the initial symptoms of small bowel adenocarcinoma, usually consisting of vague, non-specific abdominal discomfort, may contribute to diagnostic delay and result in poor patient outcome. One study attributed a delay in diagnosis of 8.2 months to the failure of the physician to order the appropriate tests (18). We found that, among patients with localized disease, those diagnosed with stages II and III had poorer outcomes compared with patients with equivalent stage colorectal cancer. Wilson et al. (19) suggests that this may be attributed to the fact that truly radical resection is generally impossible in small bowel adenocarcinoma, because of the proximity of the nodes to the vascular supply of the small bowel; this would compromise the blood supply to the remaining small bowel and right colon. In addition, patients with small bowel adenocarcinoma who are admitted with acute abdominal obstruction or bleeding are likely to undergo emergency laparotomy by a non-oncologic surgeon, making optimal radical resection generally impossible. Suboptimal resection is associated with inaccurate pathologic staging as well as poor patient outcome. Previous study reported conflicting results regarding the survival outcome according to the nodal involvement. Barenes et al. and Shefali et al. (4,11) reported no differences in 5-year survival for node-negative and -positive patients (53 versus 47%), this may have been due to limited knowledge of pathologic nodal status and/or inadequate lymphadenectomy due to supoptimal resection. We similarly observed poor survival outcomes in patients with Stages II and III tumors. Although we assessed a limited number of patients, our findings suggest that suboptimal surgery and inadequate lymphadenectomy may be associated with poor survival outcome.
To date, there are no clear associations between tumor markers and small intestine adenocarcinoma. Some patients with small intestine adenocarcinoma have been found to have elevated serum CA19-9 (20) or CEA (21) concentrations. Although no association between tumor markers and prognosis has been established, elevated CA19-9 levels have been associated with invasion to the peritoneum, as well as vascular and lymphatic involvement (18). We did not observe any significant association between tumor markers and stage or treatment outcome in patients with small intestine adenocarcinoma. Additional studies are needed to define the association between tumor markers and outcome in these patients.
We found that the 3-year survival rate of patients who underwent curative resection was 66.1%, comparable to previous reports (4–6,12). Patients who received adjuvant chemotherapy after curative resection had longer survival than patients who underwent curative resection alone, although the difference was not statistically significant (P = 0.130). The role of adjuvant chemotherapy after curative resection remains unclear. A retrospective analysis reported that adjuvant chemotherapy did not significantly affect survival on multivariate analysis (12,22). However, recurrences were observed in 40–70% of patients who underwent curative resection, with most recurrences at distant sites (11,12). Distant recurrence remains the leading cause of treatment failure, suggesting a role for adjuvant chemotherapy. We observed tumor recurrence after curative resection in 13 of the 26 patients (50%), with nine having recurrences at distant sites. To date, there have been no prospective studies assessing the role of adjuvant chemotherapy, indicating a requirement for prospective trials.
The median OS was significantly longer in patients who received palliative chemotherapy than in those who did not (8 versus 3 months, P = 0.025). In the only previous prospective trial, palliative treatment with 5-FU, adriamycin, mitomycin-C in 39 patients with metastatic small bowel adenocarcinoma resulted in a response rate of 18.4% and a median OS of 8 months (23). Retrospective analysis of an infusional 5-FU-based regimen (including ECF) showed a response rate of 37% and a median OS of 13 months (24). In addition, a first- or second-line gemcitabine and irinotecan-based regimen showed a 30–40% response rate (22). Of our 36 patients with metastatic or recurrent disease, 15 (41.7%) received palliative chemotherapy and had a median OS of 8 months. Although our analysis is retrospective and most of the chemotherapy regimens were a combination of 5-FU and cisplatin, our findings suggest that the role of palliative chemotherapy should be further evaluated. Further prospective trials using newer chemotherapy agents as palliative treatment are needed.
Curative resection is currently the only factor that can prolong patient survival. Consequently, early and accurate diagnosis is crucial to improve patient outcomes. Recently, small bowel capsule endoscopy and flexible enteroscopy have become available, initially used for suspected or known mid-gastrointestinal bleeding. Recent studies reported that 6–12% of patients with occult gastrointestinal bleeding were diagnosed with small bowel tumors (25–28). Among patients diagnosed by capsule endoscopy, 60% had malignant tumors and 20% had small bowel adenocarcinomas (25,29). In addition, flexible enteroscopy can take biopsies of suspicious areas for histopathologic diagnosis (27,28). Capsule endoscopy and enteroscopy may detect tumors at earlier stages, thus improving patient outcomes.
In conclusion, physician's suspicion and awareness of SBA is crucial to make appropriate diagnostic investigation for earlier detection and increasing resectibility of SBA. Especially in cases of obscured gastrointestinal bleeding or unexplained abdominal pain unknown origin, the physician should order appropriate diagnostic investigation. In addition, the role of adjuvant chemotherapy in patients with locally advanced disease should be evaluated prospectively because distant recurrence was the most common cause of treatment failure. Appropriate palliative chemotherapy regimens for metastatic or recurrent disease should be evaluated prospectively, too. Due to the rarity of these tumors, multi-institutional cooperation is essential for the success of these studies.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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None declared.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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