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Impact of radiologic splenic vessel invasion in resectable left-sided pancreatic ductal adenocarcinoma: predictor of early systemic recurrence following upfront surgery

Background The aim of this study is to identify prognostic factors and the best candidates for neoadjuvant therapy among patients with resectable left-sided pancreatic ductal adenocarcinoma (PDAC) by analyzing the timing and pattern of recurrence following upfront surgery. Methods This single-center retrospective study included patients with resectable left-sided PDAC who underwent upfront distal pancreatectomy from 2005 to 2015. A minimum P value approach was used to evaluate the optimal cutoff of early recurrence. The predictors of recurrence were assessed with Cox regression analysis. Results Among 311 included patients, 241 (77.5%) had a recurrence at a median follow-up of 29.3 months. Systemic recurrence occurred in 194 patients (80.5%) and isolated local recurrence in 47 patients (19.5%). A recurrence-free survival cutoff of 12 months was selected to distinguish between early and late recurrence. The patients with early recurrence had a shorter median overall survival (16.1 vs. 39.9 months, P<0.001) and post-recurrence survival (9.6 vs. 17.2 months, P<0.001) than those with late recurrence. The patients with systemic recurrence had a shorter median overall survival (19.6 vs. 29.1 months, P=0.007) and post-recurrence survival (11.0 vs. 15.3 months, P=0.024) than those with an isolated local recurrence. In multivariable analysis, preoperative CA 19-9 ≥500 U/mL [odd ratio (OR) 2.037, P=0.035], radiologic splenic vessels invasion (OR 5.014, P<0.001), positive radial resection margin (OR 2.638, P<0.001), and no adjuvant chemotherapy (OR 2.084, P=0.001) were predictors of an early systemic recurrence. Conclusions Radiologic splenic vessels invasion may be considered to indicate a biologically borderline status in patients with anatomically resectable left-sided PDAC. Future clinical trials of neoadjuvant therapy targeting these patients should be conducted.

35%. As authors mentioned, this discrepancy is often observed in clinical. However, in this trial, pathological invasion was not a predictive factor for recurrence. Therefore, authors should describe what factors radiological vessel invasion cases possibly included except pathological vessel invasion (ex. Perineural invasion).
Changes in the text: Kitamura et al. (38) suggested that radiologic and pathologic splenic artery involvement are not consistent because the periarterial plexus us thick, making it difficult for tumors to invade the arterial wall pathologically. According to our study results, although not pathologic SVs invasion, radiologic SVs invasion is a significant predictor of early systemic recurrence. Therefore, radiologic SVs invasion does not only indicate pathologic SVs invasion, but includes other factors affecting prognosis. For example, in present study, a higher perineural invasion was confirmed in patients with radiologic SVs invasion but no pathologic SVs invasion (53/64, 82.8%) than in the entire study cohorts (239/311, 76.8%). Comments 3: Authors described "did not analyze the splenic artery and splenic vein separately since the study cohort would have been heterogeneously divided into small groups". However, unless both the pathological splenic vessel invasion and radiological splenic vessel invasion are predictive factors, it may be helpful to analyze splenic artery and splenic vein separately even if they are small groups. Please add the information in Table 1 and 3.  Changes in the text: The institution of present study has been obligated to report the presence or absence of SVs invasion in pathologic reports of specimens following distal pancreatectomy since 2012. In previous reports, the presence of SVs invasion was omitted in some cases.
Comments 5: Postoperative complications such as PORF is observed more often in early recurrence group, compared with late recurrence groups. Lately, earlier adjuvant chemotherapy has been reported to be crucial in several cancers. Therefore, please check and add the duration between the surgery to adjuvant chemotherapy in Table 1  Changes in the text: Median interval between surgery and adjuvant chemotherapy for the entire cohort was 36.0 days. There was no statistically significant difference in interval between surgery and adjuvant chemotherapy between the groups. Comments 3: In the explanatory text regarding Table 1, for items with statistically significant differences, the word "significantly" should be added and the specific numerical values should be stated (as is already the case). On the other hand, for items with no statistically significant differences, it is only necessary to state that there was no significant difference, and there is no need to provide specific numerical values. This is because the text is lengthy and can be understood by looking at Table 1. In Table 3, the same things are found.

Changes in the text:
There were no statistically significant differences in age, sex, BMI, or Charlson-age comorbidity index between the groups. Preoperative CA19-9 (69.7 vs 29.9 U/mL, p=0.018) was significantly higher and the tumor size on preoperative CT (2.89 vs 2.24 cm, p<0.001) was significantly larger in patients with recurrence than in those without recurrence. The radiologic SVs invasion and combined adjacent organ resection were significantly more frequent (13.8 vs 2.9%, p=0.001) in patients with recurrence than in those without recurrence.
Patients' demographics were not significantly differed between the ER and LR groups in terms of age, sex, BMI, or Charlson age-comorbidity index. Preoperative CA19-9 (89.2 vs 36.3 U/mL, p=0.016) and CEA (2.4 vs2.0 ng/mL, p=0.018) were significantly higher in the ER group than in the LR group. The tumor size on preoperative CT (3.09 vs 2.49 cm, p=0.002) and SUVmax on preoperative FDG-PET (5.4 vs 4.0, p<0.001) were significantly larger in the ER group than in the LR group. The presence of SVI on preoperative CT was significantly more common in the ER group (78.4 vs 38.0%, p<0.001). Combined adjacent organ resection was performed significantly more frequently in the ER group than in the LR group (13.6 vs 5.1%, p=0.045). In terms of the pathologic results, lymphovascular invasion (50.6 vs 31.6%, p=0.005) and a positive radial resection margin (29.6 vs 17.7%, p=0.047) were significantly more frequent in the ER group than in the LR group. There were no