Introduction: Although several clinical applications have reported the usefulness of the radical antegrade modular pancreatosplenectomy (RAMPS) procedure for left-sided pancreatic ductal adenocarcinoma, few studies have reported the advantages of RAMPS with respect to the local recurrence (LR) rate. Methods: As of 2018, 68 and 62 patients underwent RAMPS and standard retrograde pancreatosplenectomy (SRPS). The first recurrence and all subsequent recurrence sites observed on images during a follow-up period and/or chemotherapy. The clinical variables are collected retrospectively. Results: LR only was found in 5 patients in the RAMPS group (5/68, 7.3%) and in 15 patients in the SRPS group (15/62, 24.2%; p = 0.008) as the first recurrence site. Any chemotherapies were not a risk factor for the incidence of LR. The 5-year cumulative LR rate was significantly lower in patients in the RAMPS group compared with those in the SRPS group (23.6% vs. 49.6%; p = 0.019). The 5-year overall survival was 42.2% in the RAMPS group and 33.0% in the SRPS group (p = 0.251). Conclusion: The RAMPS procedure for left-sided pancreatic ductal adenocarcinoma may reduce the LR, cumulative LR rates.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with a 5-year survival rate of only 5–10% [1, 2]. Left-sided PDAC has an even worse prognosis because of the tumor location, later awareness of clinical symptoms, and easier invasion of major vessels and adjacent organs, owing to posterior extension [3]. Only a surgical approach provides a possible cure and long-term survival, but the median overall survival (OS) is still only 17–21 months, and the 5-year survival rate is around 16–19% after curative-intent surgery [3‒5].

The postoperative local recurrence (LR) rate of PDAC is high (50%–80%) [6‒8], directly contributing to the poor prognosis. A microscopically negative tumor margin, an R0 resection, is the key to curative surgery. Radical antegrade modular pancreatosplenectomy (RAMPS), described by Strasberg et al. [9], is advocated to achieve better and clearer margins for R0 resection of the posterior extent of left-sided PDAC and may contribute to a lower LR rate. RAMPS is performed using a right-to-left antegrade approach, with early parenchymal transection at the neck of the pancreas and initial control of the splenic artery with lymphadenectomy, as well as full visualization of the retroperitoneal plane of dissection based on clear landmarks, compared with standard retrograde pancreatosplenectomy (SRPS) [9, 10].

Although several clinical applications and retrospective studies have reported the usefulness of the RAMPS procedure, including the ability to achieve negative tangential margins [11, 12], harvest more lymph nodes (LNs) [10, 13‒18], and decrease blood loss [18], few studies have reported the advantages of RAMPS with respect to the LR rate, and no study has reported regarding the cumulative LR rate. The present retrospective study assessed whether patients with left-sided PDAC undergoing RAMPS have a lower LR or cumulative LR rate than those undergoing SRPS.

Patient Selection

This retrospective cohort study of a prospectively corrected hospital surgical patient database was reviewed and approved by the institutional review board of the University of Tokyo (Approval No. 2158-9). Written informed consent was obtained for the proposed surgery. An opt-out statement was publicly disclosed (http://www.u-tokyohbp-transplant-surgery.jp/). None of the patients were opposed to being included in the present study. The data were obtained from consecutive patients who underwent distal pancreatosplenectomy at the University of Tokyo Hospital between January 2008 and December 2018.

Preoperative Evaluation

All patients were evaluated to determine the accurate location of the cancer and the presence of distant metastasis on contrast-enhanced multidetector-row computed tomography or magnetic resonance imaging. Patients with tumor invasion into the adjacent organs, portal vein, stomach, left adrenal gland, transverse colon, Gerota’s fascia, and spleen were considered as candidates for surgery. Chemotherapy was considered first for the existence of distant metastasis, dissemination, and any invasion into the superior mesenteric artery or celiac artery. Beginning in 2014, tumors encasing less than 180° of the superior mesenteric or celiac artery [19] were excluded from upfront surgery and underwent neoadjuvant chemotherapy under a borderline resectable status by a multidisciplinary team comprising board-certified gastroenterologists, radiologists, and hepato-biliary-pancreatic surgeons.

Surgical Procedure

In 2011, the RAMPS procedure was introduced to the institution for left-sided PDAC instead of the SRPS procedure. Although the SRPS procedure was mainly selected until 2013, the RAMPS procedure has dominated since 2014 based on decision by senior surgeons on a case-by-case basis. Beginning in 2018, the RAMPS procedure was selected for all patients with left-sided PDAC. Informed consent was obtained from all patients before surgery.

The SRPS procedure was performed as follows. After the lesser sac was entered to expose the distal anterior pancreas, the spleen and distal pancreas were initially mobilized up to the confluence of the superior mesenteric vein, portal vein, and splenic vein. The splenic artery and vein were then ligated and divided, and the pancreas neck was transected in the last part. The dorsal side of the pancreas is usually dissected along with the anterior renal fascia (Gerota’s fascia), but the anterior renal fascia was also partially resected when the tumor invaded the dorsal side of the pancreas [10].

In the RAMPS procedure, the splenic artery was ligated at the beginning, followed by division of the pancreatic neck. The peripancreatic dissection proceeded in a right-to-left manner, directly confirming the appropriate surgical margin for the pancreatic cancer. After completing the peripancreatic dissection, the left adrenal vein and left renal vein were usually exposed as a landmark (Fig. 1). A more detailed description of the RAMPS procedure was provided previously [12]. Anterior or posterior RAMPS was selected based on the degree of retroperitoneal tumor invasion into the area adjacent to the left adrenal grand [12]. A drain was placed at the stump of the pancreas and/or left subphrenic space in all patients [20].

Fig. 1.

Photograph obtained after completion of the RAMPS procedure. The left renal vein and left kidney are exposed as landmarks. P, pancreas stump; SMV, superior mesenteric vein; SMA, superior mesenteric artery; CHA, common hepatic artery; CA, celiac artery; LRV, left renal vein; K, kidney.

Fig. 1.

Photograph obtained after completion of the RAMPS procedure. The left renal vein and left kidney are exposed as landmarks. P, pancreas stump; SMV, superior mesenteric vein; SMA, superior mesenteric artery; CHA, common hepatic artery; CA, celiac artery; LRV, left renal vein; K, kidney.

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Data Collection

The clinical background data of each patient were collected, including age, sex, tumor location, carcinoembryonic antigen level, carbohydrate antigen 19-9 level, s-pancreas-1 antigen level, Duke pancreatic monoclonal antigen-2 level, and any treatment-related variables, including history of chemotherapy. Surgical details were also collected, including surgical time, intraoperative blood loss and transfusion, other resected organs, and postoperative hospital stays. Surgical complications were categorized according to the Clavien-Dindo classification [21]. Postoperative pancreatic fistulas were graded according to the International Study Group definition 2016 version [22]. The pathologic diagnosis was determined by experts in pancreatic tumor pathology. Pathologic data, including tumor differentiation, diameter, microscopic lymphatic invasion, vascular invasion, and neural invasion, were collected. With respect to surgical curability, R0 resection was defined as a histologically negative margin, while R1 resection was defined as a positive margin. The number of resected LNs and metastases was also evaluated. The eighth edition of the Union for International Cancer Control Staging was used for determining the TNM stage [23].

Follow-Up and the Pattern of Recurrence

The patients were followed up at outpatient clinics, and adjuvant chemotherapy was considered. Gemcitabine was mainly used until 2013, after which S-1 was mainly used. The carcinoembryonic antigen and carbohydrate antigen 19-9 tumor marker levels were measured every 3 months after surgery. All patients underwent computed tomography or magnetic resonance imaging every 3–6 months.

Recurrence was defined as a new lesion identified by any imaging procedure after surgery. Simultaneous elevation of tumor markers or positive positron emission tomography confirmed a diagnosis of recurrence. LR was defined as a new or growing soft tissue lesion in the left upper side of the retroperitoneum near the pancreatic resection stump as a previous surgical field or along the trunk of the celiac or superior mesenteric artery. Distant recurrence was defined as recurrence at any other organ, peritoneum, or beyond the regional LNs. The first recurrence site was defined as that observed on any image leading to diagnosis, and the site was recorded. All subsequent recurrence sites observed on any images were continuously recorded to evaluate the effects of chemotherapy after detecting the first recurrence site to elucidate cumulative all, local, and distant recurrence rate.

Statistical Analysis

The χ2 test was used to compare categorical data, and the Mann-Whitney U test was used for continuous data. The OS, recurrence-free survival, and cumulative recurrence rate were analyzed by the Kaplan-Meier method with a log-rank test. Logistic regression analysis as a multivariate analysis was performed to determine the independent risk factors for LR using IBM SPSS Statistics 25.0 software (International Business Machines Japan, Ltd., Tokyo, Japan). Values are expressed as the median ± range, and a p value <0.05 was considered statistically significant.

Cohort Characteristics

Between 2008 and 2018, a total of 235 patients underwent distal pancreatosplenectomy for a left-sided pancreas tumor at the University of Tokyo Hospital. Sixty-six patients who were diagnosed with benign or low-malignant potential tumor disease were excluded from the study (33 with intraductal papillary-mucinous adenomas, 13 with mucinous cystic neoplasms, 7 with solid pseudopapillary neoplasms, 6 with chronic pancreatitis, 3 with serous cystadenomas, 2 with simple pancreatic cysts, 1 with a hamartoma, and 1 with an epidermoid cyst). Another 39 patients who did not have PDAC were excluded from the analysis (27 with neuroendocrine tumors, 9 with metastatic tumors, 2 with acinar cell carcinomas, and 1 with plasmacytoma, Fig. 2).

Fig. 2.

Flowchart of patient selection. PDAC, pancreatic ductal adenocarcinoma; RAMPS, radical antegrade modular pancreatosplenectomy; SRPS, standard retrograde pancreatosplenectomy.

Fig. 2.

Flowchart of patient selection. PDAC, pancreatic ductal adenocarcinoma; RAMPS, radical antegrade modular pancreatosplenectomy; SRPS, standard retrograde pancreatosplenectomy.

Close modal

The remaining 130 patients were included in the present analysis. Of these 130 patients, 68 and 62 patients who underwent RAMPS and SRPS were assigned to the RAMPS and SRPS groups, respectively (Fig. 2). In the RAMPS group, 6 patients underwent posterior RAMPS. The clinical backgrounds, surgical outcomes, and pathologic variables of patients in each group are compared and summarized in Table 1. The clinical backgrounds did not differ between the groups, except that the RAMPS group had more patients that underwent neoadjuvant (10 vs. 1, p = 0.007) or S-1 adjuvant (36 vs. 18, p = 0.001) chemotherapy. Neoadjuvant regimens were 5 gemcitabine, S-1, leucovorin; 4 gemcitabine, nab-paclitaxel; and 1 5-fluorouracil, oxaliplatin, irinotecan in the RAMPS group and 1 gemcitabine, S-1, leucovorin in the SRPS group, without radiation.

Table 1.

Patients’ backgrounds

 Patients’ backgrounds
 Patients’ backgrounds

Surgical Outcomes and Pathological Factors

The surgical outcomes did not differ between groups. Mean operation time and blood loss were 321 min versus 320 min (p = 0.388) and 270 mL versus 310 mL (p = 0.636) in the RAMPS and SRPS groups, respectively. The combined resection rate was 16.2% versus 21.0% (p = 0.482), Clavien-Dindo classification greater than IIIa was 45.6% versus 41.9% (p = 0.675), postoperative pancreatic fistula grade B or C was 51.5% versus 50.0% (p = 0.867), and median postoperative hospital stay was 19 days versus 21 days (p = 0.272) in the RAMPS and SRPS groups, respectively. The median follow-up period for OS of the RAMPS and SRPS groups were 21 months (range: 1–94 months) and 19 months (range: 1–119 months), respectively, with no significant difference between groups (p = 0.213).

Among the pathology-related variables, the RAMPS group had a significantly better R0 resection rate (92.6% vs. 79.0%, p = 0.025) and a significantly greater number of resected LNs (21 vs. 19, p = 0.025) than the SRPS group. Other factors, including differentiation (p = 0.661), tumor diameter (p = 0.462), positive LN invasion (p = 0.360), vascular invasion (p = 0.908), neural invasion (p = 0.246), T factor (p = 0.666), N factor (p = 0.359), and final TNM stage (p = 0.405), did not differ significantly between groups.

First Recurrence Site

Overall, 37 patients in the RAMPS group and 44 patients in the SRPS group had recurrent PDAC. The first recurrence site is shown in Figure 3. LR only was found in 5 patients in the RAMPS group (5/68, 7.3%) and in 15 patients in the SRPS group (15/62, 24.2%; p = 0.008). Simultaneous local and distant recurrence was found in 8 patients in the RAMPS group (8/68, 11.8%) and in 7 patients in the SRPS group (7/62, 11.3%; p = 0.993). Distant recurrence only was found in 24 patients (24/68, 35.3%) in the RAMPS group and in 22 patients (22/62, 35.5%, p = 0.982) in the SRPS group.

Fig. 3.

First recurrence site after pancreatosplenectomy. Locoregional recurrence was found in 5 patients in the RAMPS group (5/68, 7.3%) and in 15 patients in the SRPS group (15/62, 24.2%; p= 0.008). “Both” indicates simultaneous local and distant recurrence. RAMPS, radical antegrade modular pancreatosplenectomy; SRPS, standard retrograde pancreatosplenectomy.

Fig. 3.

First recurrence site after pancreatosplenectomy. Locoregional recurrence was found in 5 patients in the RAMPS group (5/68, 7.3%) and in 15 patients in the SRPS group (15/62, 24.2%; p= 0.008). “Both” indicates simultaneous local and distant recurrence. RAMPS, radical antegrade modular pancreatosplenectomy; SRPS, standard retrograde pancreatosplenectomy.

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Cumulative Recurrence Rate

The cumulative all recurrence, cumulative LR, and cumulative distant recurrence rate were compared between the RAMPS and SRPS groups, as shown in Figure 4a–c. The 5-year cumulative all recurrence rate was 62.4% in patients in the RAMPS group and 75.6% in patients in the SRPS group (p = 0.141). The 5-year cumulative LR rate was significantly lower in patients in the RAMPS group compared with those in the SRPS group (23.6% vs. 49.6%; p = 0.019). The 5-year cumulative distant recurrence rate did not differ significantly between groups (60.2% in the RAMPS group and 60.4% in the SRPS group; p = 0.810). Of the 130 patients, 11 patients (10 RAMPS, 1 SRPS) received neoadjuvant chemotherapy, and 3 (27%) of these patients had LR, whereas among the other 119 patients (58 RAMPS, 61 SRPS), 37 (31%) had LR. The difference between the groups was not significant (Table 2, p = 0.793).

Table 2.

Risk factors for the incidence of LR

 Risk factors for the incidence of LR
 Risk factors for the incidence of LR
Fig. 4.

Kaplan-Meier curves of the cumulative all recurrence rate (a), cumulative LR rate (b), and cumulative distant recurrence rate (c) for patients in the RAMPS and SRPS groups. The 5-year cumulative LR rate was significantly lower in the RAMPS group than in the SRPS group (23.6% vs. 49.6%, respectively; p= 0.019, (b)). Kaplan-Meier curves of OS (d) and recurrence-free survival (e). The 5-year OS was 42.2% in the RAMPS group and 33.0% in the SRPS group (p= 0.251). The 5-year recurrence-free survival was 29.9% in the RAMPS group and 19.3% in the SRPS group (p= 0.114). RAMPS, radical antegrade modular pancreatosplenectomy; SRPS, standard retrograde pancreatosplenectomy.

Fig. 4.

Kaplan-Meier curves of the cumulative all recurrence rate (a), cumulative LR rate (b), and cumulative distant recurrence rate (c) for patients in the RAMPS and SRPS groups. The 5-year cumulative LR rate was significantly lower in the RAMPS group than in the SRPS group (23.6% vs. 49.6%, respectively; p= 0.019, (b)). Kaplan-Meier curves of OS (d) and recurrence-free survival (e). The 5-year OS was 42.2% in the RAMPS group and 33.0% in the SRPS group (p= 0.251). The 5-year recurrence-free survival was 29.9% in the RAMPS group and 19.3% in the SRPS group (p= 0.114). RAMPS, radical antegrade modular pancreatosplenectomy; SRPS, standard retrograde pancreatosplenectomy.

Close modal

Risk Factors for LR

Univariate analysis of risk factors for the incidence of LR revealed regional LN metastasis, positive microscopically retroperitoneal invasion, and SRPS procedure as risk factors (Table 2). Any chemotherapies were not a factor for the less LR. Multivariate analysis confirmed that the SRPS procedure was an independent risk factor for the incidence of LR (odds ratio 2.80, 95% confidence interval 1.25–6.24; p = 0.012).

Overall and Recurrence-Free Survival

The OS and recurrence-free survival curves of the 2 cohorts are shown in Figure 4d, e). The 5-year OS was 42.2% in the RAMPS group and 33.0% in the SRPS group (p = 0.251). The 5-year recurrence-free survival was 29.9% in the RAMPS group and 19.3% in the SRPS group (p = 0.114). Although the OS rate did not differ significantly between the groups, it tended to be higher in the RAMPS group than in the SRPS group.

Here, we report the largest cohort study of patients undergoing pancreatosplenectomy in a single center to date [13‒18, 24]. Our findings indicate that the LR-only rate as the first recurrence site was significantly lower in the RAMPS group than in the SRPS group despite similar patient backgrounds. Furthermore, this is the first report regarding RAMPS with a low cumulative LR rate. Multivariate regression analysis identified the SRPS procedure as an independent risk factor for the incidence of LR. The survival rate of the RAMPS group tended to be higher, but the difference between groups was not significant.

Several previous studies demonstrated an advantage of the RAMPS procedure (Table 3). The number of harvested LNs was greater in patients that underwent the RAMPS procedure compared with the SRPS procedure. Strasberg and colleagues reported the use of RAMPS for complete regional LN dissection, and the number of total retrieved LNs was 14.3 [9]. Seven retrospective studies, including the present study, reported the same advantage of the RAMPS procedure; 7.6–28.4 LNs were harvested compared with 2.8–20.7 LNs during the SRPS procedure [13‒18, 24]. Certainly, the number of harvested LNs varied widely among institutions (range 2.8–28.4), but 87.5% (7/8) studies, including the present study, reported the superiority of the RAMPS procedure [13‒18]. In addition, LN metastasis was identified as a risk factor for LR in the univariate analysis. Although LN metastasis was not identified as a risk factor in the multivariate analysis (p = 0.050), LN metastasis was an important risk factor, consistent with previous studies [7, 25, 26]. The RAMPS procedure may contribute to secure LN dissection in left-sided PDAC.

Table 3.

Review

 Review
 Review

Regarding the R0 resection rate, Abe and colleagues reported that the RAMPS procedure achieved a higher R0 rate (90.6%; n = 53) than the SRPS procedure (67.5%; n = 40) [16]. Despite reports of high R0 resection rates by Trottman et al. [15] (100%; n = 6), Park et al. [14] (89.5%; n = 38), Kim et al. [17] (84.6%; n = 30), and Huo et al. [18] (90.9%; n = 11), the rates did not differ significantly from those of other procedures in any of the studies. These outcomes were consistent with those reported by Strasberg et al. [11] (90%; n = 10) but not those reported by Lee et al. [24] (41.7%; n = 12); the final outcomes however still have not necessarily been determined. A systematic review and meta-analysis of retrospective studies showed advantages of the RAMPS procedure for achieving a higher R0 rate (p = 0.02–0.008) [27, 28] based on the studies listed in Table 3. In the present study, although both the RAMPS and SRPS procedures were curative-intent surgeries, the R0 rate differed significantly between groups (RAMPS 92.6%, n = 68 vs. SRPS 79.0%, n = 62).

Previous reports discussed the superiority of the technical aspects of the RAMPS procedure as follows. First, the RAMPS procedure proceeds in a right-to-left antegrade resection, which allows the surgeon to fully visualize the retroperitoneal plane of dissection [9, 10]. Korrel et al. [29] suggested Gerota’s fascia resection as a factor associated with improved OS from 1,200 PDAC surgery cohorts. The RAMPS procedure may contribute to obtaining a negative margin for the posterior extent of left-sided PDAC. Second, several retroperitoneal landmarks, such as the left kidney, adrenal grand, and their veins, can be dissected in the retroperitoneal plane during the RAMPS procedure [10]. By contrast, no clear anatomic landmarks in the retroperitoneal plane can be visualized by the surgeon during the SRPS procedure [11]. Third, because of early control of the splenic artery as a main in-flow to left-sided PDAC [10, 16], the RAMPS procedure may provide a bloodless surgical field [16]. These advantages of the RAMPS procedure may contribute to greater accuracy.

In the present study, although the different adjuvant chemotherapy protocols were not a significant factor in the univariate and multivariate analyses, patients in the RAMPS group underwent more S-1 adjuvant chemotherapy than those in the SRPS group. In general, the adjuvant chemotherapy agent may be difficult to deliver to the LR site because of decreased vascularity [30, 31]. To control LR, a suitable and precise surgical procedure or neoadjuvant chemotherapy [32, 33] may be more important than the adjuvant chemotherapy. When focusing simply on neoadjuvant chemotherapy, there is no definitive evidence that it reduces LR. A recent single-arm clinical study reported an 11% LR rate with gemcitabine, S-1, and radiation neoadjuvant therapy [34]. Another retrospective study showed no difference: a 29% LR rate with neoadjuvant chemotherapy and a 28% LR rate with upfront surgery for borderline resectable PDAC [35]. In the present study, only 11 (8.4%) patients underwent neoadjuvant chemotherapy, and 3 (27%) of them had LR, whereas among patients who underwent upfront surgery with no radiation, 37 (31%) had LR, and there was no significant difference between groups (p = 0.793). Another recent randomized study reported a 17% total LR rate, but details were not provided [33]. Further studies and a full report are needed to elucidate the contribution of neoadjuvant chemotherapy to reducing LR in PDAC patients.

Although the survival rate of the RAMPS procedure tended to be higher, neither OS nor recurrence-free survival was significantly different between groups in the present study. Huo et al. [18] reported a meta-analysis based on a retrospective analysis of 7 single centers [13‒17, 24] (listed in Table 3 in the present paper), indicating that the RAMPS procedure was associated with only slightly better OS than the SRPS procedure (hazard ratio: 0.65, 95% confidence interval: 0.43–0.99, p = 0.046). In the present study, the patient cohort may be too small. Given the fact that advances in perioperative chemotherapy have improve PDAC treatment outcomes, surgical procedure alone may be difficult to improve prognosis. A prospective clinical study with a larger patient cohort is necessary to confirm the potential advantage of the RAMPS procedure for improving OS and recurrence-free survival.

The present study has several limitations. The present study has several limitations. This study was a retrospective study with a small number of patients. Furthermore, the study did not have a randomized design and may have included a random error or historical bias. As there was no clear case selection regarding the surgeon’s choice of SRPS or RAMPS, the present study also may have a selection bias. The single or 2-operator setting may guarantee superior long-term outcomes, and lymphadenectomy around the superior mesenteric artery may be more extended in RAMPS than that in SRPS, which could contribute to reduce LR. The perioperative chemotherapy protocol was not the same among study periods, and the increased rate of neo-, S-1 adjuvant chemotherapy in the RAMPS group may have contributed to the superior outcomes in this group. These factors might also influence LR. Thus, the present outcome should be carefully interpreted. As no prospective studies have been reported, a prospective study with a suitable patient cohort size is needed to confirm the differences between the RAMPS and SRPS procedures with the same perioperative chemotherapy protocol [36].

The present study demonstrated that the RAMPS procedure for left-sided PDAC may reduce the LR and cumulative LR rate.

We thank Prof. Yoshihiro Sakamoto in Kyorin University for important contribution to RAMPS procedure.

This study protocol was reviewed and approved by the institutional review board of the University of Tokyo (Approval No. 2158-9). Written informed consent was obtained for the proposed surgery. An opt-out statement was publicly disclosed (http://www.u-tokyohbp-transplant-surgery.jp/). None of the patients were opposed to being included in the present study. The study protocol was in accordance with the ethical standards of the institutional research committee and the 1964 Helsinki Declaration.

The authors of this manuscript do not have any conflicts of interest to declare.

This work was supported by Grant No. 19K09191 (Kaneko) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. There were no external funding resources or grants from the other authors.

Conception and design: S.K. and J.K. Analysis and interpretation: J.A., T.I., and N.A. Drafting the manuscript: S.K. and J.K. Critical revision of the manuscript: J.A., T.I., N.A., and K.H. All the authors approved the final version of the manuscript for submission.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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