Abstract
Objectives
The histologic response to neoadjuvant chemoradiotherapy (nCRT) has been intimately related to outcomes in locally advanced rectal cancer. Serum carcinoembryonic antigen (CEA) levels change after nCRT and after surgery as compared with before nCRT.
Methods
The subjects were 149 patients with locally advanced rectal cancer who received nCRT between 2005 and 2013. The patients were divided into 4 groups according to the serum CEA levels: group 1, 55 patients with negative serum CEA levels before nCRT; group 2, 41 patients with positive serum CEA levels before nCRT that became negative after nCRT; group 3, 37 patients with positive serum CEA levels after nCRT that became negative after surgery; and group 4, 16 patients with positive serum CEA levels after nCRT as well as after surgery.
Results
Pathological complete response, T downstaging, and tumor shrinkage were significantly higher in group 1 than in other groups. Disease-free survival was significantly poorer in group 4. The lack of a decrease in the serum CEA level in group 4 was most likely attributed to the persistence of micrometastases outside the resection field.
Conclusions
Changes in serum CEA levels measured before nCRT, after nCRT, and after surgery can be used to reliably predict the histologic response to nCRT and outcomes.
Keywords: Rectal cancer, Chemoradiotherapy, Carcinoembryonic antigen, Histologic response, Disease-free survival, Overall survival
Introduction
Carcinoembryonic antigen (CEA), a glycoprotein with a molecular weight of approximately 180,000 that is produced and secreted by colorectal cancer cells, was reported by Gold and Freedman [1] in 1965. Serum CEA is a representative tumor marker for colorectal cancer and has been widely used for surveillance after colorectal cancer surgery according to the guidelines of the American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), and the National Comprehensive Cancer Network (NCCN) [2, 3, 4, 5].
Many studies have reported that patients with colorectal cancer who had negative serum CEA levels before surgery have better outcomes than patients with positive serum CEA levels [6, 7, 8, 9]. However, the preoperative serum CEA level has also been reported to be unrelated to outcomes. The results thus remain controversial [10]. Patients with rectal cancer who had positive serum CEA levels before surgery and in the early postoperative period have been reported to have a higher recurrence rate and poorer outcomes than patients whose serum CEA levels became negative in the early postoperative period [11, 12, 13]. Multidisciplinary treatment including neoadjuvant chemoradiotherapy (nCRT) is the standard treatment for locally advanced rectal cancer, resulting in tumor downstaging and decreasing the rate of local recurrence [14, 15].
Patients who have a good histologic response to nCRT and those who have tumor downstaging (responders) have low rates of local recurrence and distant metastasis and good outcomes [16, 17, 18, 19]. It is thus clinically important to establish factors that can be used to predict the response to nCRT and outcomes. However, reliable factors have yet to be established. Serum CEA levels have been studied as a candidate predictive factor. Several studies have reported that the serum CEA level before nCRT is related to the histologic response [9, 20, 21], whereas another study found no relation between these factors [22]. The serum CEA level after nCRT has been reported to be related to the treatment response by some studies [22, 23], whereas another study found no relation between these factors [24]. In patients with rectal cancer who receive CRT, the clinical significance of serum CEA as a predictor of the treatment response and outcomes has not been established.
Serum CEA levels can be measured before CRT, after CRT, and after surgery. Serum CEA levels may fluctuate after nCRT and after surgery as compared with the levels before nCRT and before surgery. We therefore studied the relations of the serum CEA levels before starting nCRT, after the completion of nCRT, and after resection of the primary lesion to the histologic response and outcomes.
Patients and Methods
Patients
We treated 180 patients with rectal adenocarcinoma of the middle and lower rectum (clinical T3/T4, Nx, M0 or clinical T2, N+, M0) who received nCRT followed by curative surgery in the Department of Surgery, Tokai University from 2005 through 2013. We studied 149 of these patients whose serum CEA levels were measured before nCRT, after nCRT, and after surgery. The median follow-up of the surviving patients was 60.4 months. The initial evaluation included digital examination of the rectum, colonoscopy, barium enema, computed tomography of the chest, abdomen and pelvis, endorectal ultrasonography, and magnetic resonance imaging (MRI) of the pelvis.
Chemoradiotherapy
Preoperative radiotherapy was performed with an 18-MV X-ray beam delivered by a linear accelerator (Clinac 2100C, Varian Medical Systems, Inc., Palo Alto, CA, USA), using the four-field technique. Irradiation was carried out once (1.8 or 2 Gy) daily, until reaching a total dose of 40–45 Gy.
Surgery was done 6–8 weeks after the completion of radiotherapy. Concomitant chemotherapy was started at the same time as radiotherapy. Fifteen patients received oral uracil/tegafur (400 mg/m2), and 134 received oral S-1 (80 mg/m2). Oral uracil/tegafur was given for 5 days, followed by a 2-day rest. This cycle was repeated. Oral S-1 was given for 2 consecutive weeks followed by a 1-week rest and then was given for 2 more weeks [25, 26].
Assessment of Tumor Response
Tumor response was evaluated on the basis of the histological findings of the resected specimens. The Tumor Regression Grade (TRG) classification was used to evaluate histological regression [27]. Marked regression was defined as grade 2 (presence of rare residual cancer cells) or grade 1 (complete regression) according to the TRG criteria. The rates of shrinkage of tumor diameter and tumor volume were calculated on the basis of the results of barium enema examination and MRI findings of the pelvis before starting therapy and immediately before surgery [28].
Measurement of Serum CEA Levels
Serum CEA was assayed with the E-test “TOSOH” II CEA system (TOSOH Inc., Tokyo, Japan), using a high-affinity anti-CEA monoclonal antibody. The cutoff value of CEA was set at 5 ng/mL.
Grouping of Patients according to Serum CEA Levels
Patients who had negative serum CEA levels before starting nCRT were assigned to group 1. Patients who had positive serum CEA levels before nCRT that became negative after the completion of nCRT were assigned to group 2. Patients who had positive serum CEA levels after nCRT that became negative after surgery were assigned to group 3. Patients who had positive serum CEA levels after nCRT as well as after surgery were assigned to group 4.
Statistical Analysis
All statistical analyses were performed using JMP® 11 software (SAS Institute Inc., Cary, NC, USA). χ2 tests, Fisher exact tests, independent t tests, or one-way analysis of variance (ANOVA) were implemented to analyze variables. Disease-free survival (DFS) and overall survival (OS) from the time of surgery were calculated by the Kaplan-Meier method, using log-rank tests for comparison. For the multivariate analysis, a Cox proportional hazards model was used to calculate hazard ratios and 95% confidence intervals. p values of less than 0.05 were considered to indicate statistical significance.
This study was approved by the institutional review board of our University (08R-032), and all patients provided their written informed consent.
Results
Patient demographics are summarized in Table 1. Of the 149 patients, 116 (78%) were male. The median age was 64 years (range, 32–92). The serum CEA level before nCRT was less than 5 ng/mL in 55 patients (36.9%) and 5 ng/mL or higher in 94 patients (63.1%). Table 2 (part A) shows the relation between the serum CEA level before nCRT and the response to nCRT. Patients who had a serum CEA level of less than 5 ng/mL had significantly higher rates of a pathological complete response (ypCR), T downstaging, and tumor shrinkage on MRI than did patients who had a serum CEA level of 5 ng/mL or higher. Table 2 (part B) shows the relation between the serum CEA level after nCRT and the response to nCRT. Patients who had a serum CEA level of less than 5 ng/mL had a higher rate of tumor shrinkage than did patients who had a serum CEA level of 5 ng/mL or higher. The serum CEA level was unrelated to the ypCR rate and the T downstaging rate.
Table 1.
Patient demographics
| Total (n = 149) | Serum CEA levels before nCRT |
p | ||
|---|---|---|---|---|
| <5 ng/mL (n = 55) | ≥5 ng/mL (n = 94) | |||
| Median age (range), years | 64 (32 – 92) | 63 (34 – 76) | 64 (32 – 92) | 0.643 |
| Gender | 0.419 | |||
| Male | 116 (77.9) | 45 (81.8) | 71 (75.5) | |
| Female | 33 (22.1) | 10 (18.2) | 23 (24.5) | |
| Smoking status | 0.382 | |||
| Never + previously | 96 (64.4) | 38 (69.1) | 58 (61.7) | |
| Currently | 53 (35.6) | 17 (30.9) | 36 (38.3) | |
| Tumor location | 0.087 | |||
| Middle rectum | 62 (41.6) | 28 (50.9) | 34 (36.2) | |
| Lower rectum | 87 (58.4) | 27 (49.1) | 60 (63.8) | |
| Histologic grade | 0.451 | |||
| Well | 98 (65.8) | 40 (72.7) | 58 (61.7) | |
| Moderate | 48 (32.2) | 15 (27.3) | 33 (35.1) | |
| Poor | 1 (0.7) | 0 | 1 (1.1) | |
| Others | 2 (1.3) | 0 | 2 (2.1) | |
| Surgical procedure | 0.054 | |||
| LAR | 111 (74.5) | 46 (83.6) | 65 (69.1) | |
| APR | 38 (25.5) | 9 (16.4) | 29 (30.9) | |
| cT classification | 0.464 | |||
| cT2 | 11 (7.4) | 2 (3.6) | 9 (9.6) | |
| cT3 | 112 (75.2) | 43 (78.2) | 69 (73.4) | |
| cT4 | 26 (17.4) | 10 (18.2) | 16 (17.0) | |
| cN classification | 0.374 | |||
| cN0 | 50 (33.6) | 21 (38.2) | 29 (30.9) | |
| cN1 – 2 | 99 (66.4) | 34 (61.8) | 65 (69.1) | |
Figures are n (%) unless indicated otherwise. CEA, carcinoembryonic antigen; nCRT, neoadjuvant chemoradiotherapy; LAR, low anterior resection; APR, abdominoperineal resection.
Table 2.
Relations of serum CEA levels before and after nCRT to histological response or tumor shrinkage rate
| <5ng/mL | ≥5ng/mL | p | |
|---|---|---|---|
| A Serum CEA levels before nCRT | (n = 55) | (n = 94) | |
| YpCR | 0.014 | ||
| + | 13 (23.6) | 8 (8.5) | |
| − | 42 (76.4) | 86 (91.5) | |
| T downstaging | 0.017 | ||
| + | 34 (61.8) | 38 (40.4) | |
| − | 21 (38.2) | 56 (59.6) | |
| Tumor shrinkage rate on MRI, % | 77.9 ± 2.6 | 69.8 ± 2.0 | 0.014 |
| B Serum CEA levels after nCRT | (n = 94) | (n = 55) | |
| ypCR | 0.47 | ||
| + | 15 (16.0) | 6 (10.9) | |
| − | 79 (84.0) | 49 (89.1) | |
| T downstaging | 0.19 | ||
| + | 50 (53.2) | 22 (40.0) | |
| − | 44 (46.8) | 33 (60.0) | |
| Tumor shrinkage rate on MRI, % | 76.0 ± 1.9 | 66.5 ± 2.6 | 0.004 |
Figures are n (%) unless indicated otherwise. CEA, carcinoembryonic antigen; nCRT, neoadjuvant chemoradiotherapy; ypCR, pathologic complete response.
The clinicopathological characteristics of the 4 groups of patients classified according to the serum CEA levels before nCRT, after nCRT, and after surgery are shown in Table 3. The number of patients was 55 (37%) in group 1, 41 (27%) in group 2, 37 (25%) in group 3, and 16 (11%) in group 4. After surgery, the serum CEA level increased to 5 ng/mL or higher in 4 patients (2.7%): 1 patient in group 1 and 3 patients in group 2. These patients were dealt in the initial groups.
Table 3.
Clinicopathological characteristics according to CEA group
| Group 1 (n = 55) | Group 2 (n = 41) | Group 3 (n = 37) | Group 4 (n = 16) | p | |
|---|---|---|---|---|---|
| Median age (range), years | 63 (34 – 76) | 62 (32 – 80) | 67 (37 – 81) | 63 (43 – 92) | 0.327 |
| Gender | 0.221 | ||||
| Male | 45 (81.8) | 27 (65.9) | 31 (83.8) | 13 (81.3) | |
| Female | 10 (18.2) | 14 (34.1) | 6 (16.2) | 3 (18.7) | |
| Smoking status | 0.167 | ||||
| Never + previously | 38 (69.1) | 30 (73.2) | 19 (51.3) | 9 (56.3) | |
| Currently | 17 (30.1) | 11 (26.8) | 18 (48.7) | 7 (43.7) | |
| Tumor location | 0.143 | ||||
| Middle rectum | 28 (50.9) | 18 (43.9) | 10 (27.0) | 6 (37.5) | |
| Lower rectum | 27 (49.1) | 23 (56.1) | 27 (73.0) | 10 (62.5) | |
| Histologic grade | 0.081 | ||||
| Well | 40 (72.7) | 21 (51.2) | 25 (67.6) | 12 (75.0) | |
| Moderate | 15 (27.3) | 19 (46.3) | 11 (29.7) | 3 (18.7) | |
| Poor | 0 | 0 | 0 | 1 (6.3) | |
| Others | 0 | 1 (2.5) | 1 (2.7) | 0 | |
| cT classification | 0.851 | ||||
| cT2 | 2 (3.6) | 4 (9.8) | 3 (8.1) | 2 (12.5) | |
| cT3 | 43 (78.2) | 30 (73.2) | 28 (75.7) | 11 (68.8) | |
| cT4 | 10 (18.2) | 7 (17.0) | 6 (16.2) | 3 (18.7) | |
| cN classification | 0.065 | ||||
| cN0 | 21 (38.2) | 8 (19.5) | 17 (45.9) | 4 (25.0) | |
| cN1 – 2 | 34 (61.8) | 33 (80.5) | 20 (54.1) | 12 (75.0) | |
| ypCR | 13 (23.6) | 3 (7.3) | 3 (8.1) | 2 (12.5) | 0.094 (0.014a) |
| ypT classification | 0.026 | ||||
| ypT0 – 1 | 22 (40.0) | 8 (19.5) | 6 (16.2) | 2 (12.5) | |
| ypT2 – 4 | 33 (60.0) | 33 (80.5) | 31 (83.8) | 14 (87.5) | |
| ypN classification | 0.007 | ||||
| ypN0 | 49 (89.1) | 25 (61.0) | 25 (67.6) | 11 (68.8) | |
| ypN1 – 2 | 6 (10.9) | 16 (39.0) | 12 (32.4) | 5 (31.2) | |
| TRG | 0.001 | ||||
| 1 – 2 (marked regression) | 30 (54.5) | 17 (41.5) | 6 (16.2) | 4 (25.0) | |
| 3 – 5 (nonmarked regression) | 25 (45.5) | 24 (58.5) | 31 (83.8) | 12 (75.0) | |
| Surgical procedure | <0.001 | ||||
| LAR | 46 (83.6) | 36 (87.8) | 23 (62.2) | 6 (37.5) | |
| APR | 9 (16.4) | 5 (12.2) | 14 (37.8) | 10 (62.5) |
Figures are n (%) unless indicated otherwise. CEA, carcinoembryonic antigen; ypCR, pathologic complete response; TRG, tumor regression grade; LAR, low anterior resection; APR, abdominoperineal resection.
Group 1 versus groups 2 – 4.
A ypCR was obtained in 13 patients (23.6%) in group 1, 3 patients (7.3%) in group 2, 3 patients (8.1%) in group 3, and 2 patients (12.5%) in group 4, with no significant difference among the 4 groups (p = 0.094). However, the ypCR rate was significantly higher in group 1 than in groups 2–4 (p = 0.014). The number of patients with a ypT stage of 0 or 1 was 22 (40.0%) in group 1, 8 (19.5%) in group 2, 6 (16.2%) in group 3, and 2 (12.5%) in group 4 and was significantly higher in group 1 (p = 0.026). The number of patients with a ypN stage of 0 was 49 (89.1%) in group 1, 25 (61.0%) in group 2, 25 (67.6%) in group 3, and 11 (68.8%) in group 4 and was significantly higher in group 1 (p = 0.007). The number of patients in whom aTRG of 1 or 2 was obtained (i.e., histologic responders) was 30 (54.5%) in group 1, 17 (41.5%) in group 2, 6 (16.2%) in group 3, and 4 (25.0%) in group 4. The histologic responder rate was significantly higher in groups 1 and 2 (p = 0.001).
Figure 1 shows the DFS and OS according to group. The 5-year DFS rate was 75.9% in group 1, 74.6% in group 2, 77.0% in group 3, and 48.2% in group 4 and was significantly lower in group 4 than in the other 3 groups (p = 0.024). The 5-year OS rate was 88.0% in group 1, 90.8% in group 2, 85.4% in group 3, and 67.9% in group 4, with no significant difference among the groups (p = 0.138). When the groups were compared, the 5-year OS rate was significantly lower in group 4 than in group 1 and group 2 (p = 0.03 and p = 0.019), but did not differ significantly between group 3 and group 4 (p = 0.125).
Fig. 1.
Disease-free survival (DFS) and overall survival (OS) according to the CEA group.
Table 4 shows the results of Cox regression analysis of DFS and OS in each CEA group. The hazard ratio for DFS was 3.25 in group 4 and was significantly higher than that in the other groups. The hazard ratio for OS was 3.41 in group 4 and was slightly but not significantly higher than the values in the other groups.
Table 4.
Hazard ratio (HR) of the CEA groups for disease-free survival and overall survival
| Disease free survival |
Overall survival |
|||
|---|---|---|---|---|
| HR (95% CI) | p | HR (95% CI) | p | |
| Group 1 | 1 | 1 | ||
| Group 2 | 1.22 (0.55 – 2.70) | 0.617 | 1.06 (0.34 – 3.20) | 0.913 |
| Group 3 | 1.08 (o.47 – 2.46) | 0.849 | 1.43 (0.50 – 4.18) | 0.500 |
| Group 4 | 3.25 (l.33 – 7.59) | 0.011 | 3.41 (1.00 – 10.88) | 0.051 |
The association of clinical and treatment-related factors in DFS is shown in Table 5. The patients' age, sex, smoking status, histologic grade, clinical T classification, clinical N classification, ypN classification, and surgical procedure were not significantly associated with DFS on univariate analysis. Multivariate analysis revealed that group 4 in serum CEA groups was the only poor prognostic factor in DFS.
Table 5.
Univariate and multivariate analyses to identify clinical and treatment factors associated with disease-free survival
| Disease-free survival |
|||||
|---|---|---|---|---|---|
| n (%) | 5-year | univariate (p) | HR (95% CI) | multivariate (p) | |
| Age | 0.321 | ||||
| ≤60 years | 63 (42.3) | 0.673 | |||
| >60 years | 86 (57.7) | 0.764 | |||
| Gender | 0.887 | ||||
| Male | 116 (77.9) | 0.719 | |||
| Female | 33 (22.1) | 0.749 | |||
| Smoking status | 0.465 | ||||
| Never + previously | 96 (64.4) | 0.711 | |||
| Currently | 53 (35.6) | 0.750 | |||
| Tumor location | 0.046 | ||||
| Middle rectum | 62 (41.6) | 0.819 | 1.0 | ||
| Lower rectum | 87 (58.4) | 0.655 | 1.56 (0.82 – 3.15) | 0.181 | |
| Histologic grade | 0.400 | ||||
| Well | 98 (65.8) | 0.727 | |||
| Moderate | 48 (32.2) | 0.748 | |||
| Poor/others | 3 (2.0) | 0.333 | |||
| cT classification | 0.901 | ||||
| cT2 | 11 (7.4) | 0.727 | |||
| cT3 | 112 (75.2) | 0.718 | |||
| cT4 | 26 (17.4) | 0.763 | |||
| cN classification | 0.233 | ||||
| cN0 | 50 (33.6) | 0.788 | |||
| cN1 – 2 | 99 (66.4) | 0.694 | |||
| ypCR | 0.040 | ||||
| Residual disease | 128 (85.9) | 0.689 | 1.0 | ||
| ypCR | 21 (14.1) | 0.950 | 0.83 (0.10 – 7.10) | 0.851 | |
| ypT classification | 0.006 | ||||
| ypT0 – 1 | 38 (25.5) | 0.919 | 1.0 | ||
| ypT2 – 4 | 111 (74.5) | 0.661 | 2.53 (0.73 – 15.95) | 0.161 | |
| ypN classification | 0.098 | ||||
| ypN0 | 110 (73.8) | 0.751 | |||
| ypN1 – 2 | 39 (26.2) | 0.651 | |||
| TRG | 0.016 | ||||
| 1 – 2 (marked regression) | 57 (38.3) | 0.846 | 1.0 | ||
| 3 – 5 (non-marked regression) | 92 (61.7) | 0.652 | 1.30 (0.61 – 3.12) | 0.518 | |
| Surgical procedure | 0.098 | ||||
| LAR | 111 (74.5) | 0.767 | |||
| APR | 38 (25.5) | 0.602 | |||
| CEA group | 0.002 | ||||
| Groups 1 – 3 | 133 (89.3) | 0.755 | 0.40 (0.20 – 0.90) | 0.029 | |
| Group 4 | 16 (10.7) | 0.482 | 1.0 | ||
CEA, carcinoembryonic antigen; ypCR, pathologic complete response; TRG, tumor regression grade; LAR, low anterior resection; APR, abdominoperineal resection.
Discussion
In patients with rectal cancer who receive nCRT, a lower serum CEA level before nCRT has been reported to be associated with a better histologic response [9, 20, 21, 24, 29, 30, 31, 32, 33, 34] and better outcomes [9, 35, 36]. As for the relation between the serum CEA level after nCRT and the histologic response, some studies have reported a high rate of ypCR among patients with negative serum CEA levels [22, 23, 37], whereas another study found no relation between the serum CEA level after nCRT and response [24]. Consistent results have thus not been obtained. One study has reported that patients with a low serum CEA level after nCRT have good outcomes [22]. As for the relations of the serum CEA levels before nCRT and after nCRT to outcomes, several studies have reported thatpatients with high serum CEA levels before as well as after nCRT have poor outcomes [37, 38, 39, 40]. However, another study has reported that patients with a low rate of decrease in the serum CEA level after nCRT have poor outcomes [41].
In our study, patients who had a serum CEA level of less than 5 ng/mL before nCRT had significantly higher rates of ypCR, T downstaging, and tumor shrinkage on MRI than did patients who had a serum CEA level of 5 ng/mL or higher. These results are consistent with the previously reported finding that patients who have negative serum CEA levels before treatment have a good histologic response to nCRT. In addition, patients who had positive serum CEA levels before treatment that became negative after nCRT (group 2) had a significantly better histologic response (TRG) to nCRT than did patients whose serum CEA levels became negative after resection of the primary lesion (group 3) and patients who continued to have positive serum CEA levels even after surgery (group 4). These results are attributed to the fact that nCRT decreased CEA production by the primary lesionin group 2, resulting in a negative serum CEA level.
As for the relation between the serum CEA level after nCRT and the histologic response, various results have been reported. To our knowledge, however, no previous study has compared the histologic response among clearly defined subgroups of patients classified according to the serum CEA levels after nCRT and before surgery as well as the serum CEA levels after nCRT and after surgery.
Given that CEA is produced only by the primary lesion, in patients who had a poor histologic response to nCRT (groups 3 and 4), the serum CEA level remained high after nCRT, but the serum CEA level after surgery should have decreased in response to surgical resection of the primary lesion. In our study, the serum CEA level in 16 patients (11%) did not become negative even after resection of the primary lesion (group 4). Group 4 had significantly poorer DFS than did groups 1, 2, and 3. These findings are probably attributed to the fact that patients in group 4 had micrometastases that continued to produce CEA even after resection of the primary lesion. The serum CEA level did not become negative in this group, and outcomes were consequently poor. Therefore, positive serum CEA levels after resection of the primary lesion suggest the presence of micrometastases persisting after resection of the primary tumor and may indicate the need for appropriate systemic chemotherapy.
The DFS rate did not differ between patients who had negative serum CEA levels before nCRT (group 1) and patients in whom the serum CEA became negative after nCRT or resection of the primary lesion (groups 2 and 3). However, the histologic response to nCRT was significantly better in patients who had negative serum CEA levels before nCRT (group 1) than in the other groups. The underlying mechanism remains unclear.
The limitations of the present study include the relatively small sample size. Larger prospective, multicenter studies are needed to confirm our results.
Conclusions
In patients with rectal cancer who received nCRT, the serum CEA level before nCRT was intimately related to the histologic response of the primary lesion. Comparison of the serum CEA levels before nCRT, after nCRT, and after surgery allowed patients who continued to have positive serum CEA levels after surgery to be defined as a subgroup of patients with a poor prognosis who would most likely benefit from appropriate systemic chemotherapy.
Disclosure Statement
Gota Saito, Sotaro Sadahiro, Takashi Ogimi, Hiroshi Miyakita, Kazutake Okada, Akira Tanaka, and Toshiyuki Suzuki have reported no potential conflicts of interest.
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