Even though significant improvements have achieved in surgical techniques and perioperative management, esophageal anastomotic leakage still constitutes one of the most common and serious PCs. According to a recent large-scare cohort study and multicenter phase II studies, the prevalence of EJAL for laparoscopic total gastrectomy range from 1.7 to 5.7% [21–23]. In this study, the incidence of EJAL was 11.4% (95% CI 5.6–17.2%), higher than data reported by former research. Some factors may lead to this difference. First of all, the patients included in this study were all AEG. It was recommended that lower mediastinal lymph nodes should be dissection through transhiatal approach for Siewert type II or III AEG, if there was esophageal invasion of 3 cm or less [24, 25]. A retrospective research suggested that the optimal proximal margin length for Siewert type II and III AEG was 2 cm (2.8 cm in vivo) [26]. Hence,the scope of resection was wider and the location of anastomosis was higher, compared with other sites originated gastric cancer. These differences resulted in more operation difficulty and longer operation time. The multivariate analysis suggested that operation time longer than 360 minutes significantly increased the risk of major PCs (OR 6.753, 95% CI 2.037–22.395, p = 0.002). This finding was consistent with other studies [27–29]. Secondly, the pathologic stage of patients enrolled in this study were much later. Nearly half of the patients were at pathologic stage III. Advanced stage was an independent risk factor for anastomotic leakage [28]. In addition, our research revealed that proximal gastrectomy with double-tract anastomosis increased the risk of EJAL (OR 8.224, 95% CI 1.976–34.234, p = 0.004). However, a latest meta-analysis consisted of 592 patients found that laparoscopic proximal gastrectomy with double-tract reconstruction (PG-DTR) had comparable short-term outcome with laparoscopic total gastrectomy (TG) [30]. As a novel reconstruction procedure considered superior to TG in term of nutrition, the clinical outcomes of PG-DTR were controversial. There still needs high-quality evidence to confirm the safety of PG-DTR.
PCs prolonged the time of hospitalization and increased mortality rate. In our research, the median hospitalization period significantly prolonged in major PCs group, compared than no/minor PCs group (33 vs. 8, p༜0.001). It was reported that PCs was also a risk factor for poor prognosis[4–6]. A latest meta-analysis comprised of 12,065 patients revealed that the pooled HR (95% CI) for complications regarding OS was 1.79 (1.39, 2.30). Csenders et al. developed a classification of anastomotic leakage according to onset of septic complications. The mortality rate of type I (subclinical, no septic complications) was 5%. While the mortality rate of type II (clinical, with septic complications) was up to 78% [31]. Another factor influenced the successful management of EJAL was the early detection. Clinical manifestations of EJAL, such as thoracic or abdominal pain, respiratory failure, pneumonia, pleural effusion, and arrhythmia were less descriptive. The presence of digestive fluids and oral colorant in surgical drains or positive result of postoperative contrast swallow was unequivocal evidence of EJAL. But the false negative result rate was up to 40% [32]. Endoscopy can be utilized for both diagnosis and endoscopic treatment of EJAL [33]. However, endoscopic examination at incorrect time can worsen the pre-existent EJAL [34]. Thus, it is of great importance to find a new factor to exclude the onset of EJAL.
C-reactive protein (CRP) was the first reported acute-phase protein in 1930. CRP was synthesized by hepatocytes quickly upon the inflammatory stimulation. CRP levels peaked at 48 hours after the initiation of an acute inflammatory response [35, 36]. This feature was consistent with our result that the mean CRP level in no/minor PCs group peaked at postoperative day 2 and reduced to baseline gradually. Thus, an abnormal elevated serum CRP level can be utilized to indicate the presence of postoperative infectious complications. What’s more, elevated CRP levels were ahead of the onset of descriptive clinical manifestation and positive imaging findings.
There have been some studies investigated the cut-off values of CRP at a certain day to predict the leakage of anastomosis. But the reported cut-off values of CRP varied greatly,ranging from 78 to 229 mg/L on POD 1 to 5 [7–16]. As a systematic inflammatory factor, CRP levels varied individually according to age, sex, nutrient status, and operation [17–20]. Therefore, the diagnostic accuracy of postoperative serum CRP level on a certain day was not that exact. To the best of our knowledge, this is the first research using the variation tendency of serum CRP to exclude PCs after laparoscopic gastrectomy for AEG. And we did find that the ratio of CRP on postoperative day 3 to postoperative day 2 had the best accuracy to exclude anastomotic leakage (AUC 0.903 95% CI 0.814–0.993, p༜0.001) compared than other inflammatory factor.
PCT was another biomarker detected to exclude EJAL and believed to be a more specific marker of severe infections and complications [37, 38]. As shown in Fig. 1d, the mean PCT level of no/minor PCs were at their highest on postoperative day 1 and declined to baseline in a few days. The PCT levels of major PCs maintained above normal range even though effective antibiotics had been used. However, the diagnostic accuracy of PCT wasn’t good as CRP. Because the positive predictive value of PCT was too low. The diagnostic accuracy calculated by Youden’s index should consider both the negative predictive value and positive predictive value.
The limitations of this study include its retrospective and single-institution design. Prospective studies should be performed to investigate whether early diagnostic or therapeutic approaches based on variation tendency of postoperative CRP levels could actually lead to earlier detection of infectious complications and improve outcomes. Due to the strict inclusion criteria, the sample size of this study was small. However, as stated above, strict enroll criteria can minimalize the variation of postoperative CRP levels.